Sulfonylbenzene compounds as anti-inflammatory/analgesic agents

ABSTRACT

This invention provides a compound of the formula:  
                 
 
     or its pharmaceutically acceptable salt thereof, wherein A is partially unsaturated or unsaturated five membered heterocyclic, or partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (I) are attached to ring atoms of Ring A, which are adjacent to each other; R 1  is optionally substituted aryl or heteroaryl, with the proviso that when A is pyrazole, R 1  is heteroaryl; R 2  is C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkylamino, C 1-4  dialkylamino or amino; R 3 , R 4  and R 5  are independently hydrogen, halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl or the like; or two of R 3 , R 4  and R 5  are taken together with atoms to which they are attached and form a 4-7 membered ring; R 6  and R 7  are independently hydrogen, halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylamino or N,N-di C 1-4  alkylamino; and m and n are independently 1, 2, 3 or 4.  
     This invention also provides a pharmaceutical composition useful for the treatment of a medical condition in which prostaglandins are implicated as pathogens.

TECHNICAL FIELD

[0001] This invention relates to compound and pharmaceuticalcompositions for the treatment of cyclooxygenase mediated diseases. Thecompounds of this invention inhibit the biosynthesis of prostaglandinsby intervention of the action of the enzyme cyclooxygenase onarachidonic acid, and are therefore useful in the treatment oralleviation of inflammation and other inflammation associated disorders,such as arthritis, in mammals. This invention also relates topharmaceutical compositions comprising such compounds.

BACKGROUND ART

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used intreating pain and the signs and symptoms of arthritis because of theiranalgesic and anti-inflammatory activity. It is accepted that commonNSAIDs work by blocking the activity of cyclooxygenase (COX), also knownas prostaglandin G/H synthase (PGHS), the enzyme that convertsarachidonic acid into prostanoids. Prostaglandins, especiallyprostaglandin E₂ (PGE₂), which is the predominant eicosanoid detected ininflammation conditions, are mediators of pain, fever and other symptomsassociated with inflammation. Inhibition of the biosynthesis ofprostaglandins has been a therapeutic target of anti-inflammatory drugdiscovery. The therapeutic use of conventional NSAIDs is, however,limited due to drug associated side effects, including life threateningulceration and renal toxicity. An alternative to NSAIDs is the use ofcorticosteriods, however, long term therapy can also result in severeside effects.

[0003] Recently, two forms of COX were identified, a constitutiveisoform (COX-1) and an inducible isoform (COX-2) of which expression isupregulated at sites of inflammation (Vane, J. R.; Mitchell, J. A.;Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.;Willoughby, D. A. Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 isthought to play a physiological role and to be responsible forgastrointestinal and renal protection. On the other hand, COX-2 appearsto play a pathological role and to be the predominant isoform present ininflammation conditions. A pathological role for prostaglandins has beenimplicated in a number of human disease states including rheumatoid andosteoarthritis, pyrexia, asthma, bone resorption, cardiovasculardiseases, dysmenorrhea, premature labour, nephritis, nephrosis,atherosclerosis, hypotension, shock, pain, cancer, and Alzheimerdisease. The NSAIDs currently on market inhibit both isoforms of COXwith little variation for selectivity, explaining their beneficial(inhibition of COX-2) and deleterious effects (inhibition of COX-1). Itis believed that compounds that would selectively inhibit thebiosynthesis of prostaglandins by intervention of the induction phase ofthe inducible enzyme COX-2 and/or by intervention of the activity of theenzyme COX-2 on arachidonic acid would provide alternate therapy to theuse of NSAIDs or corticosteriods in that such compounds would exertanti-inflammatory effects without the adverse side effects associatedwith COX-1 inhibition.

[0004] A variety of sulfonylbenzene compounds which inhibit COX havebeen disclosed in patents publications (WO 97/16435. WO 97/14691, WO96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO96/936617. WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845,and EP 554829): Especially, International Publication Number WO 97/11704discloses pyrazole compounds substituted by optionally substituted aryl.

BRIEF DISCLOSURE OF THE INVENTION

[0005] The present invention provides a compound of the followingformula:

[0006] or its pharmaceutically acceptable salt thereof, wherein

[0007] A is partially unsaturated or unsaturated five memberedheterocyclic, or partially unsaturated or unsaturated five memberedcarbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenylin the formula (I) are attached to ring atoms of Ring A adjacent to eachother;

[0008] R¹ is aryl or heteroaryl, and the aryl or heteroaryl beingoptionally substituted by one to four substituents selected from halo.C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylcarbonyl, hydroxy, nitro, cyano and amino, with the proviso that when Ais pyrazole, R¹ is heteroaryl.

[0009] R² is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl. C₁₋₄ alkylamino,C₁₋₄ dialkylamino or amino;

[0010] R³, R⁴ and R⁵ are independently hydrogen, halo. C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, Con alkoxy,hydroxy-C₁₋₄ alkyl, Con alkoxy C₁₋₄ alkyl, C₁₋₄ alkanoyl; cyano, nitro,cyano C₁₋₄ alkyl, carboxy, C₁₋₄ alkoxycarbonyl, aminocarbonyl, N—C₁₋₄alkylaminocarbonyl, N,N-di-C₁₋₄ alkylaminocarbonyl, N-arylaminocarbonyl,N,N-diarylaminocarbonyl, N—C₁₋₄ alkyl-N-arylamiocarbonyl, aryl, aryloxy,aryloxy-C₁₋₄ alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-C₁₋₄ alkyl,morpholino-carbonyl, C₁₋₄ alkoxyaminocarbonyl or C₁₋₄alkyl-carbonylamino; or two of R³, R⁴ and R⁵ are taken together withatoms to which they are attached and form a 4-7 membered ring;

[0011] R⁶ and R⁷ are independently hydrogen, halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, Conalkylamino, N,N-di C₁₋₄ alkylamino, hydroxyl-C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl, C₁₋₄ alkyl-C₁₋₄ alkoxy, C₁₋₄ alkylamino-C-₁₋₄ alkyl,hydroxy, amino-C₁₋₄ alkyl and N,N-di C₁₋₄ alkylamino-C₁₋₄ alkyl; and

[0012] m and n are independently 1, 2, 3 or 4.

[0013] The sulfonylbenzene compounds of the present invention exhibitinhibition of COX activity. Preferable compounds of this inventionexhibit inhibitory activity against COX-2, with more preferablecompounds having COX-2 selectivity.

[0014] Accordingly, the present invention also provides a pharmaceuticalcomposition, useful for the treatment of a medical condition in whichprostaglandins are implicated as pathogens, which comprises a compoundof the formula (I) and the pharmaceutically acceptable salts thereof.

[0015] Further, the present invention provides a method for thetreatment of a medical condition in which prostaglandins are implicatedas pathogens, in a mammalian subject, which comprises administering tosaid subject a therapeutically effective amount of said pharmaceuticalcomposition.

[0016] The medical conditions in which prostaglandins are implicated aspathogens, include the relief of pain, fever and inflammation of avariety of conditions including rheumatic fever, symptoms associatedwith influenza or other viral infections, common cold, low back and neckpain, dysmenorrhea, headache, toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis including rheumatoid arthritis,degenerative joint disease (osteoarthritis), gout, ankylosingspondylitis, systemic lumpus erythematosus and juvenile arthritis,bursitis, burns, injuries followings surgical and dental procedures.

[0017] The compounds and pharmaceutical composition of this inventionmay inhibit cellular neoplastic transformations and metastatic tumorgrowth and thus may be used in the treatment and/or prevention ofcancers in the colon, breast, skin, esophagus, stomach, urinary bladder,lung and liver. The compounds and pharmaceutical composition of thisinvention were used in the treatment and/or prevention ofcyclooxygenase-mediated proliferation disorders such as which occur indiabetic retinopathy and tumor angiogenesis.

[0018] The compounds and pharmaceutical composition of this inventionmay inhibit prostaniod-induced smooth muscle contraction by preventingthe synthesis of contractile prostanoids, and thus may be of use in thetreatment of dysmenorrhea, premature labor, asthma and eosinophilrelated disorders and in the treatment of neurodegenerative diseasessuch as Alzheimer's and Parkinson's disease, and for the treatment ofbone loss (treatment of osteoarthritis), stroke, seizures, migraine,multiple sclevosis, AIDS and encephaloathy.

[0019] By virtue of the COX-2 activity and/or specificity for COX-2 overCOX-1, such compounds will prove useful as an alternative toconventional NSAIDs particularly where such NSAIDs may becontra-indicated such as in patients with ulcers (such as peptic ulcersand gastric ulcers), gastritis, regional enterotis, ulcerative colitis,diverticulitis or with a recurrent history of GI lesions, GI bleeding,coagulation disorders including anemia such as hypoprothrombinemia,haemophilia and other bleeding problems; kidney disease; prior tosurgery of taking of anticoagulants.

[0020] This invention also provides a compound of formula:

[0021] or its salt thereof, wherein R² is C₁₋₄ alkyl, halo-substitutedC₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ dialkylamino or amino; R⁸ isindependently hydrogen, halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, N,N-di C₁₋₄ alkylamino,C₁₋₄ alkylamino-C₁₋₄ alkyl, N,N-di C₁₋₄ alkylamino-C alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl or hydroxy-C₁₋₄ alkyl; and m is 2, 3 or 4, with theproviso that R⁸ is not chloro nor trifluoromethyl.

DETAILED DISCLOSURE OF THE INVENTION

[0022] As used herein, the term “halo” is fluoro, chloro, bromo or iodo.

[0023] As used herein, the term “C₁₋₄ alkyl” means straight or branchedchain saturated radicals of 1 to 4 carbon atoms, including, but notlimited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl.

[0024] As used herein, the term “halo-substituted alkyl” refers to analkyl radical as described above substituted with one or more halogensincluded, but not limited to, chloromethyl, dichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, andthe like.

[0025] As used herein, the term “C₂₋₅ alkenyl” means straight orbranched chain unsaturated radicals of 2 to 5 carbon atoms, including,but not limited to ethenyl, 1-propenyl, 2-propenyl(allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0026] As used herein, the term “C₂₋₅ alkynyl” is used herein to meanstraight or branched hydrocarbon chain radicals having one triple bondincluding, but not limited to, ethynyl, propynyl, butynyl, and the like.

[0027] As used herein the term “aryl” means aromatic radicals such asphenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl and the like.

[0028] As used herein “heteroaryl” group usually has one heteroatomselected from O, S and N in the ring. In addition to said heteroatom,the aromatic group may optionally have up to four N atoms in the ring.For example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g.,1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl,1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), tetrazole, quinolyl, isoquinolyl,benzothienyl, benzofuryl, indolyl, and the like.

[0029] As used herein, the term “partially unsaturated or unsaturatedfive membered carbocyclic” means aromatic or non-aromatic ring-shapedradicals, for example, cyclopentenyl, cyclopent-1,3-dienyl,oxocyclopentenyl, and the like.

[0030] Examples of “partially unsaturated or unsaturated five memberedheterocyclic” are thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxolinyl, thiolinyl,pyrazolinyl, imidazolinyl, pyrrolinyl, furanone, and the like.

[0031] Preferred compounds of this invention are those of the formula(I) wherein A is partially unsaturated or unsaturated five memberedheterocyclic.

[0032] Further preferred compounds of this invention are those of theformula (I) wherein A is thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxolinyl, thiolinyl,pyrazolinyl, imidazolinyl, pyrrolinyl or furanone.

[0033] much preferred compounds of this invention are those of theformula (I) wherein A is thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl or furanone; and

[0034] R³, R⁴ and R⁵ are independently hydrogen, halo, C₄ alkyl,halo-substituted C₁₋₄ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₁₋₄ alkoxy,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₁₋₄ alkanoyl, cyano, nitro,cyano C₁₋₄ alkyl, carboxyl. C₁₋₄ alkoxycarbonyl, aminocarbonyl, N—C₁₋₄alkylaminocarbonyl, N,N-di-C₁₋₄ alkylaminocarbonyl, morpholino-carbonyl,C₁₋₄ alkoxyaminocarbonyl or C₁₋₄ alkyl-carbonylamino.

[0035] Among these, preferred compounds of this invention are those ofthe formula (I) wherein A is thienyl, oxazolyl, furyl, pyrrolyl,thiazolyl, imidazolyl, isoxazolyl, pyrazolyl or furanone;

[0036] R¹ is phenyl or heteroaryl selected from pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl,oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, tetrazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazole, quinolyl, isoquinolyl,benzo[b]thienyl, benzo[b]furyl and indolyl, and the phenyl or heteroarylbeing optionally substituted by one to three substituents selected fromhalo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylcarbonyl, C₁₋₅ alkoxycarbonyl, hydroxy, nitro, cyano and amino;

[0037] R² is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl or amino;

[0038] R³, R⁴ and R⁵ are independently hydrogen, halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₂₋₅ alkenyl, C₁₋₄ alkoxy, hydroxy-C₁₋₄alkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₁₋₄ alkanoyl, cyano, nitro, cyano C₁₋₄alkyl, carboxy, C₁₋₄ alkoxycarbonyl, aminocarbonyl, morpholino-carbonyl,C₁₋₄ alkoxyaminocarbonyl or C₁₋₄ alkyl-carbonylamino; and

[0039] R⁶ and R⁷ are independently hydrogen, halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, hydroxyl-C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkyl-C₁₋₄ alkoxy, C₁₋₄alkylamino-C₁₋₄ alkyl or hydroxy; and

[0040] m and n are independently 1 or 2.

[0041] Further preferred compounds of this invention are those of theformula (I) wherein A is thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl,imidazolyl, isooxazolyl, pyrazolyl or furanone;

[0042] R¹ is phenyl or heteroaryl selected from pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl,oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, benzo[b]thienyl,benzo[b]furyl and indolyl, and the phenyl or heteroaryl being optionallysubstituted by halo, C₁₋₄ alkyl, C₁₋₄ alkyl carbonyl or C₁₋₄ alkoxycarbonyl;

[0043] R² is methyl, ethyl, fluoromethyl, difluoromethyl or amino;

[0044] R³, R⁴ and R⁵ are independently hydrogen, halo, C₁₋₄ alkyl,fluoro-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy-C₁₋₄ alkyl, C₁₋₄alkanoyl, cyano, nitro, cyano C₁₋₄ alkyl, carboxy, C₁₋₄ alkoxycarbonyl,morpholino-carbonyl, C₁₋₄ alkoxyaminocarbonyl or C₁₋₄alkyl-carbonylamino; and

[0045] R⁶ and R⁷ are independently hydrogen, halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxyl-C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl, C alkyl-C₁₋₄ alkoxy, C₁₋₄ alkylamino-C₁₋₄ alkyl orhydroxy.

[0046] Also, further preferred compounds of this invention are those ofthe formula (I) wherein A is thienyl, oxazolyl, furyl, pyrrolyl,thiazolyl, imidazolyl, isooxazolyl, pyrazolyl or furanone;

[0047] R¹ is phenyl or heteroaryl selected from pyridyl, pyrimidinyl,thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl,benzo[b]thienyl and benzo[b]furyl, and the phenyl or heteroaryl beingoptionally substituted by one to three substituents selected fromfluoro, chloro, methyl, ethyl, propyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, methoxyl, acetyl, ethylcarbonyl,methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl;

[0048] R² is methyl, fluoromethyl or amino;

[0049] R³, R⁴ and R⁵ are independently hydrogen, fluoro, chloro, methyl,ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,ethoxyl, hydroxymethyl, hydroxyethyl, methylcarbonyl, cyano, nitro,cyanomethyl, cyanoethyl, carboxy, methoxylcarbonyl, ethoxycarbonyl,morpholinocarbonyl, methoxyaminocarbonyl or methylcarbonylamino; and

[0050] R⁶ and R⁷ are independently hydrogen, fluoro, chloro, methyl,ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,ethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl,ethoxymethyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl,aminomethyl, aminoethyl or hydroxy.

[0051] Among these, preferred compounds of this invention are those ofthe formula (I) wherein A is oxazolyl, pyrrolyl, imidazolyl, isoxazolyl,pyrazolyl or furanone;

[0052] R¹ is phenyl or heteroaryl selected from pyridyl, pyrimidinyl,thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, benzothienyland benzofuryl, and the heteroaryl being optionally substituted bychloro or methyl;

[0053] R² is methyl, fluoromethyl or amino;

[0054] R³, R⁴ and R⁵ are independently hydrogen, methyl,trifluoromethyl, hydroxymethyl, cyano, cyanomethyl, carboxy,ethoxycaroblyl, morpholinocarbonyl, methoxyaminocarbonyl ormethylcarbonylamino; and

[0055] R⁶ and R⁷ are independently hydrogen, fluoro, chloro, methyl,methoxy, hydroxymethyl, ethoxy, trifluoromethyl, methoxymethyl,methyaminomethyl, aminomethyl or hydroxy.

[0056] Also, preferred compounds of this invention are those of theformula (I) wherein

[0057] A is pyrazolyl or furanone;

[0058] R¹ is heteroaryl selected from thienyl, furyl, oxazolyl andthiazolyl;

[0059] R² is methyl or amino;

[0060] R³, R⁴ and R⁵ are independently hydrogen, methyl ortrifluoromethyl;

[0061] R⁶ and R⁷ are independently hydrogen, fluoro, chloro, methyl ormethoxy; and

[0062] m and n are 1.

[0063] Preferred individual compounds of this invention are:

[0064]1-[4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0065]1-[4-(methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0066]1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0067]1-[4-(methylsulfonyl)phenyl]-5-[4-(benzo[b]furan-2-yl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0068]4-[5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0069]4-[5-[4-(3-thienyl)phenyl]-4-cyano-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0070]4-[5-[4-(4-pyridyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0071]4-[5-[4-(3-pyridyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0072]4-[5-[4-(5-methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0073]4-[5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0074]4-[5-[4-(5-pyrimidinyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0075]4-[5-[4-(2-pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0076]4-[5-[4-(2-benzothienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0077]4-[5-[4-(5-acetylthiophene-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0078]4-[5-[4-(3-pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0079]4-[5-[4-(3-methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0080] methyl1-[4-(sulfamoylphenyl]-5-[4-(3-thienyl)phenyl]-1H-pyrazole-3-carboxylate;

[0081]4-[3-(cyanomethyl)-5-[4-(3-thienyl)phenyll]-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0082]4-[3-(hydroxymethyl)-5-[4-(3-thienyl)phenyl]-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0083]1-[4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0084]4-[5-[4-(2-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0085]1-[4-(methylsulfonyl)phenyl]-5-[4-(2-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0086]4-[5-[4-(5-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0087]1-[4-(methylsulfonyl)phenyl]-5-[4-(5-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0088]4-[5-[4-(5-chloro-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0089]4-[5-[4-(1H-imidazol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide,

[0090]4-[5-[4-(2,5-dimethylpyrrol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0091]4-[5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0092]4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0093]1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methylphenyl]-3-trifluoromethyl-1H-pyrazole;

[0094]4-[5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0095]3-[4-(3-thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone;

[0096]3-[4-(2-thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone;

[0097]3-[4-(3-furyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone;

[0098]5-[3-fluoro-4-(methylsulfonyl)phenyl]-1-[4-(2-furyl)phenyl]-2-methyl-1H-pyrrole;

[0099]5-[3-fluoro-4-(methylsulfonyl)phenyl]-1-[4-(3-furyl)phenyl]-2-methyl-1H-pyrrole;

[0100]2,3-dimethyl-1-[4-(3-furyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0101]5-[4-(methylsulfonyl)phenyl]-1-[4-(3-furyl)phenyl]-2-methyl-1H-pyrrole;

[0102]1-[4-(3-furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0103]1-[4-(2-furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0104]1-[3-chloro-4-(3-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0105]1-[3-chloro-4-(2-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0106] 1-(4-biphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0107]1-[4-(2-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0108]2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thienyl)phenyl]-1H-pyrrole;

[0109]2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(3-thienyl)phenyl]-1H-pyrrole;

[0110]2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-pyrrolyl)phenyl]-1H-pyrrole;

[0111]2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[[4-(1-tert-butoxycarbonyl)-2-pyrrolyl]phenyl]-1H-pyrrole;

[0112]2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thiazolyl)phenyl]-1H-pyrrole;

[0113]2-methyl-5-[4-(methylsulfonyl)phenyl]-4-[4-(2-thienyl)phenyl]oxazole;

[0114]4-[4-(2-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;

[0115]1-[4-(methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

[0116]2-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

[0117] 2-[4-(2-furyl)phenyl]-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole;

[0118]1-[4-(3-furyl)phenyl]-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0119]2-[4-(3-furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole,

[0120] 2-biphenyl-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0121]1-[4-(2-furyl)phenyl]-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0122]2-[4-(2-furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0123]2-[4-(2-furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;

[0124]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0125]1-[4-(fluoromethylsulfonyl)phenyl]]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0126]4-[5-[4-(2-furyl)phenyl]4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole;

[0127] 4-[5-[4-(2-furyl)phenyl]-3-hydroxymethyl1-][4-(methylsulfonyl)phenyl]-1H-pyrazole;

[0128]3-cyanomethyl-4-[5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole;

[0129] ethyl5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate;

[0130]5-[4-(1-imidazolyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol;

[0131]5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylicacid;

[0132] 2-[4-(2-furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene;

[0133] 2-[4-(3-furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene;

[0134]4-[5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0135]1-[4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0136]4-[5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0137]4-[5-[3-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0138]1-[4-(Methylsulfonyl)phenyl]-5-[3-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0139]4-[5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0140]-[4-(methylsulfonyl)phenyl]-5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0141]4-[5-[4-(2-furyl)-2-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide:

[0142]1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-2-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0143]4-[5-[2-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0144]1-[4-(methylsulfonyl)phenyl]-5-[2-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0145]1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0146]1-[4-(methylsulfonyl)phenyl]-5-[4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0147]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0148]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0149]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0150]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0151]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0152] methyl1-(4-sulfamoylphenyl)-5-[4-(2-thiazolyl)phenyl]-1H-pyrazole-3-carboxylate;

[0153]4-[4-cyano-5-[4-(2-thiazolyl)phenyl]-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0154]4-[4-chloro-5-[4-(2-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide;

[0155]5-[2-fluoro-4-(2-furyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0156]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-2-methylphenyl]-3-trifluoromethyl-1H-pyrazole;

[0157]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0158]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;

[0159]4-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;

[0160]2-{4-[f-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;

[0161]2-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;

[0162]4-[5-[4-(1,3-oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0163]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0164]4-[5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0165]4-{4-[1-[3-methyl-4-(methylsulfonyl)phenyl)]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0166]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-2-methyl-1,3-thiazole;

[0167]2-fluoro-4-[5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0168]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-5-methyl-1,3-thiazole;

[0169]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-fluorophenyl}-1,3-thiazole;

[0170]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-thiazole;

[0171]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-thiazole;

[0172]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-oxazole;

[0173]4-{2-chloro-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0174]4-{4-[f-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-oxazole;

[0175]4-{2-methoxy-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl)}-1,3-oxazole;

[0176]4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl)}-1,3-oxazole;

[0177]2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0178]2-fluoro-4-[5-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0179]4-{4-[1-[3-hydroxymethyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0180]4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0181]4-[5-[3-methoxy-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0182]4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0183]4-{2-chloro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0184]4-{2-methoxy-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0185]2-fluoro-4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0186]2-fluoro-4-[5-[3-chloro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0187]2-fluoro-4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0188]4-{2-fluoro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0189]4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0190] ethyl1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate;

[0191]1-[3-ethoxy-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicacid;

[0192]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicacid;

[0193]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-hydroxymethyl-1H-pyrazole;

[0194]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(4-morpholinecarbonyl)-1H-pyrazole;

[0195] N-methyl-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;

[0196]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;

[0197]N,N-dimethyl-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;

[0198]N-methoxy-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;

[0199]5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0200]5-[4-(2-furyl)phenyl]-1-[3-methoxy-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0201]2-fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0202]4-[5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-fluorobenzenesulfonamide;

[0203]2-fluoro-4-[5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0204]2-chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0205]3-fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0206][5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-2-methylphenyl]-3-trifluoromethyl-1H-pyrazole;

[0207]4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbenzenesulfonamide;

[0208]2-chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0209]-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-methylbenzenesulfonamide;

[0210][5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-2-methoxy]phenyl]-3-trifluoromethyl-1H-pyrazole;

[0211][5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0212]4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methoxybenzenesulfonamide;

[0213]2-chloro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0214]3-fluoro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0215]5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-[4-(4-thiazolyl)phenyl]-1H-pyrrole;

[0216]5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-[3-methyl-4-(4-thiazolyl)phenyl]-1H-pyrrole;

[0217]1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[4-(4-thiazolyl)phenyl]-4-trifluoromethyl-1H-imidazole;

[0218]2-fluoro-4-[2-[4-(4-thiazolyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

[0219]1-[3-chloro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0220]5-[5-[4-(2-furyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanol;

[0221]5-[4-(2-furyl)phenyl]-1-[3-methyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0222]1-[3-chloro-4-(methylsulfonyl)phenyl]-5-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0223]5-[4-(2-furyl)phenyl]-1-[3-(methoxymetyl)-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0224]N-[5-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)benzyl]-N-methylaminehydrochloride;

[0225][5-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanaminehydrochloride;

[0226]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole;

[0227]4-cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole;

[0228]N-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl]-1H-pyrazol-4-yl]acetamide;

[0229]4-[3-fluoro-4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone;

[0230]5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone;

[0231]2-fluoro-4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-furanyl]benzenesulfonamide;

[0232]4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]isoxazole;

[0233]5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole;

[0234]4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]isoxazole;

[0235]4-{5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide;

[0236]2-fluoro-4-{5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide;

[0237]5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole;

[0238]2-fluoro-4-[5-[3-hydroxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0239]2-fluoro-4-[5-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0240]2-fluoro-4-[5-[4-(1,3-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0241]4-[2-ethyl-4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl]-1,3-thiazole;

[0242]1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[3-methyl-4-(4-thiazolyl)phenyl]4-trifluoromethyl-1H-imidazole;

[0243]2-fluoro-4-[4-methyl-2-[4-(4-thiazolyl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide;

[0244]5-[3-chloro-5-methyl-4-(4-thiazolyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0245]4-chloro-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[3-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0246]4-[4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone;

[0247]4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-franyl]benzenesulfonamide;

[0248]5,5-dimethyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone;

[0249]2-methyl-4-[4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-thiazole;

[0250]1-[4-(methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0251]1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;

[0252]2-fluoro-4-[5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl]benzenesulfonamide;

[0253]5-methyl-3-[4-(methylsulfonyl)phenyl]-4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole;

[0254]4-[3-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl]benzenesulfonamide;

[0255]3-methyl-5-[4-(methylsulfonyl)phenyl]-4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole;

[0256]2-fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide;

[0257]2-fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide;

[0258]3-(Difluoromethyl)-2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1H-pyrazol-1-yl]benzenesulfonamide;

[0259]2-Fluoro-4-[5-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0260]2-Fluoro-4-[5-[2-chloro-4-1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;and

[0261]2-Fluoro-4-[5-[3-ethyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.

[0262] most preferred individual compounds are:

[0263]2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0264]4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0265]3-fluoro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0266]4-{2-chloro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;

[0267]2-fluoro-4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0268]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0269]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-thiazole;

[0270]4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0271]4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

[0272]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0273]1-[4-(Methylsulfonyl)phenyl]-5-[3-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0274]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0275]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0276]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0277]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;

[0278]4-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;

[0279]4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-thiazole;

[0280]4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;

[0281]2-fluoro-4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-furanyl]benzenesulfonamide;and

[0282]1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[4-(4-thiazolyl)phenyl]-4-trifluoromethyl-1H-imidazole.

[0283] Also, preferred intermediates of this invention is selected from

[0284] 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride;

[0285] 3-methoxy-4-(methylsulfonyl)phenylhydrazine hydrochloride;

[0286] 3-fluoro-4-sulfamoylphenylhydrozine hydrochloride;2-fluoro-4-sulfamoylphenylhydrazine hydrochloride;

[0287] 2-methyl-4-(methylsulfonyl)phenylhydrazine hydrochloride;

[0288] 3-methyl-4-sulfamoylphenylhydrozine hydrochloride;

[0289] 2-methyl-4-sulfamoylphenylhydrozine hydrochloride;

[0290] 2-methoxy-4-(methylsulfonyl)phenylhydrazine hydrochloride;

[0291] 3-methoxy-4-sulfamoylphenylhydrozine hydrochloride;

[0292] 3-hydroxymethyl-4-(methylsulfonyl)phenylhydrazine hydrochloride;and

[0293] 3-methyl-4-(methylsulfonyl)phenylhydrazine hydrochloride.

General Synthesis

[0294] The compounds of general formula (I) can be prepared by a varietyof synthetic routes. The following representative examples as describedhereinafter are illustrative and are not meant to limit the scope of theinvention in anyway. Unless otherwise stated, A, R¹, R², R³, R⁴, R⁵, R⁶and R⁷ are as defined herein before.

[0295] 1) Synthesis of Compound (I) by A Ring Formation

[0296] Compound (I) can be synthesized by a variety of A ring formationmethods.

[0297] Pyrazole:

[0298] When A is a pyrazole ring, the pyrazole (Ia) can be prepared froman appropriate 1,3-diketone or its equivalents (2 or 3) andphenylhydrazine (4), as shown in scheme I.

[0299] In step 1, ketone (1) is treated with a base (e.g., NaOMe, NaHand Me₃Si₂NLi preferably NaOMe, wherein Me represents methyl) and anacylating reagent (e.g., ester or ester equivalent such asacylimidazole, dialkylamide and dialkylacetal), in a solvent such asdiethylether, tetrahydrofuran, methanol, dichloromethane and methyltert-butyl ether, to form the 1,3-diketone (2) or 1,3-diketoneequivalent (3) (G¹ is OH or NR₂:R=C₁₋₄ alkyl). X in Scheme I is R¹,chloro, bromo or OH.

[0300] In step 2, the 1,3-diketone (2) or 1,3-diketone equivalent (3) istreated with the salt (such as hydrochloride, hydrobromide, sulfate andoxalate) or the free base of the hydrazine derivative (4) in ananhydrous protic solvent such as ethanol or acetic acid at refluxtemperature for from 2 hours to 20 hours to afford the pyrazole compound(Ia).

[0301] The starting materials (I) are either commercially available orcan be prepared by the method described in Aust. J. Chem., 1977, 30, 229and Heterocycles, 1990, 31 1951 and which are incorporated by reference.The regio isomeric pyrazole (Ia′) can be also prepared from thecorresponding 1,3-diketone (5) or 11,3-diketone equivalent (6) andphenyhydrazine (7), which is well known in the art.

[0302] Furanone:

[0303] Furanone (Ib) can be prepared from aryl bromomethyl ketone (8)and aryl acetic acid (9).

[0304] As shown in Scheme II, an appropriately substituted arylbromomethyl ketone (8) is reacted with an appropriately substitutedarylacetic acid (9) in a solvent such as acetonitrile,dimethylsulfoxide, dimethoxyethane and diethylether in the presence of abase such as triethylamine and diisopropylethylamine and then treatedwith 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the furanone(Ib). The α-bromomethylketone (8) can be easily obtained by halogenationof the corresponding acetophenone, which is well known in the art.

[0305] Furanone (Ib) can be also prepared by the reaction of α-hydroxyketone (10) with (11) (X═OH) in the presence of coupling reagent such as1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide andmetho-p-toluenesulfonate, and further treatment with a base such as DBU.

[0306] Imidazole:

[0307] Imidazole (Ic) can be prepared by the reaction of amidine (14)and α-haloketone (15) followed by the dehydration as shown in SchemeIII.

[0308] In step 1, the reaction of substituted nitrile (12) with primaryphenylamine (13) in the presence of alkylaluminium reagents such astrimethylaluminium, triethylaluminium, diethylaluminium chloride,diethylaluminium chloride in the presence of inert solvents such astoluene, benzene and xylene, gives amidine (14).

[0309] In step 2 the reaction of amidine (14) with α-haloketone (15)(where X is bromo or chloro) in the presence of base, such as sodiumbicarbonate, potassium carbonate, sodium carbonate and potassiumbicarbonate, or hindered tertiary amines such asN,N′-diisopropylethylamine in the presence of inert solvents such asisopropanol, acetone, and dimethylformamide at a temperature of about 0°C. to about 120° C. for 30 min. to 2 days, preferably at a temperatureof about 20° C. to about 100° C. for 30 min. to 8 hours, gives the4,5-dihydroImidazole (16).

[0310] The obtained 4,5-dihydroImidazole (16) may be dehydrated in thepresence of an acid catalyst such as 4-toluenesulfonic acid,trifluoroacetic acid and mineral acids (such as hydrochloric acid) toform the 1,2-disubstituted Imidazole (Ic) of this invention (step 3). Asuitable solvent for this dehydration step are e.g., toluene, xylene orbenzene. A compound of (Ic) wherein R² is amino can be prepared by usinga compoud of (Ic) wherein R² is methyl, for example by the Huang method(Tetrahedron Left., 1994, 35, 7201.).

[0311] In some cases the intermediate (16) may not be readily isolated.The reaction, under the conditions described above, proceeds to give theImidazole (Ic) directly.

[0312] Pyrrole:

[0313] Pyrrole can be prepared by the Paal-Knorr's method, which is wellknown in the art (scheme IV).

[0314] The preparation of suitable 1,4-diketone (19) by the Stetterreaction (for a review on Stetter reaction, Angew. Chem., Int. Ed. Engl.1976, 15, 639.) followed by heating with appropriate amines (20) in thePaal-Knorr condensation gives the pyrrole (Id). The Stetter reaction ofsubstituted benzaldehyde (17) with α,β-unsaturated ketone (18) using thethiazolium salt catalyst in the presence of bases such as triethylamine,diisopropylethylamine and pyridine, gives the 1,4-diketone (19).Suitable solvents for this reaction are methanol, ethanol orisopropanol. The reaction may be carried out at temperatures of about 0°C. to about 120° C. for 15 minutes to 2 days, preferably at temperaturesof about 20° C. to about 90° C. for 30 minutes to 1 days. Thecondensation of 1,4-diketone (19) with arylamine (20) in the presence ofan acid catalyst such as 4-toluenesulfonic acid gives the pyrrole (Id).Suitable solvents for this condensation step are e.g., toluene, xyleneor benzene. A compound of (Id) wherein R² is amino can be prepared byusing a compoud of (Id) wherein R² is methyl, for example by the Huangmethod (Tetrahedron Lett. 1994, 35, 7201.).

[0315] Alternatively, the pyrrole (Id) can be prepared as shown inScheme V.

[0316] In step 1, an aldimine (23) can be prepared by the dehydrationcondensation of a benzaldehyde (21) with an aniline (22) in an inertsolvent. The reaction is normally and preferably effected in thepresence of a solvent. Examples of suitable solvents include aliphatichydrocarbons such as hexane and heptane; aromatic hydrocarbons such asbenzene and toluene; halogenated hydrocarbons such as methylene chlorideand chloroform; ether such as diethyl ether, tetrahydrofuran anddioxane; alcohol such as methanol, ethanol and isopropanol. Among thesesolvents, the alcohol would be preferable. This reaction can be carriedout at a temperature of from 5° C. to 200° C., preferably from roomtemperature to 150° C. for from 10 minutes to 20 hours, more preferablyfrom 1 hour to 15 hours.

[0317] In step 2, an anilinonitrile (24) can be prepared by an additionof hydrogen cyanide to the aldimine (23), prepared as described instep 1. The reaction may be carried out by reacting the aldimine (23)with trimethylsilyl cyanide (TMS-CN) in the presence of a Lewis acid,for example, aluminium chloride, tin chloride and zinc chloride in aninert solvent such as diethyl ether, tetrahydrofuran, dioxane, benzene,and methylene chloride, preferably diethyl ether and tetrahydrofuran.This reaction can be carried out at a temperature of from 5° C. to 200°C., preferably from room temperature to 150° C. for from 10 minutes to50 hours, more preferably from 1 hour to 20 hours.

[0318] In step 3 and 4, the pyrrole (Id) can be prepared by reacting theanilinonitrile (24), prepared as described in step 2, with anα,β-unsaturated aldehyde or ketone (25) to obtain a pyrrolidine compound(26), which can be then dehydrated and dehydrogencyanated.

[0319] In step 3, the reaction may be carried out by reacting theanilinonitrile (24) with an α,β-unsaturated aldehyde or ketone (25) inthe presence of a base, such as lithium amide, sodium amide, potassiumamide, lithium bis(trimethylsilyl)amide, and sodium methoxide,preferably lithium bis trimethylsilyl)amide in an inert solvent such asdiethyl ether, tetrahydrofuran, dioxane, benzene, and methylenechloride, preferably diethyl ether and tetrahydrofuran. This reactioncan be carried out at a temperature of from −78° C. to 100° C.,preferably from −78° C. to room temperature for from 10 minutes to 30hours, preferably from 1 hour to 15 hours.

[0320] In step 4, the pyrroles (Id) can be prepared by the dehydrationand dehydrogencyanation of the pyrrolidine compound (26). This may beachieved by heating the crude product obtained by evaporation of thesolvent from the product of step 3, or by heating the crude materialobtained by the extraction, at a temperature of from 80° C. to 250° C.,in the presence or absence of a solvent after completion of the reactionof step 3. Suitable solvent would be toluene, xylene, diglyme, diphenylether, dimethylformamide or the like.

[0321] Oxazole:

[0322] Oxazole (Ie) can be prepared according to the followingprocedures of Scheme VI.

[0323] In step 1, the ketone (29) can be prepared by the reaction ofacid halide (27) with 4-sulfonylbenzyl halide (preferably X═Cl or Br)(28) in the presence of metal such as zinc and magnesium, preferablyzinc, in an inert solvent such as 1,2-dimethoxyethane, dioxane, diethylether, tetrahydrofuran, methylene chloride, benzene, and toluene at atemperature of from 0° C. to 150° C., preferably from room temperatureto 50° C. for from 10 minutes to 30 hours, preferably from 1 hour to 15hours. Suitable catalyst e.g., tetrakis(triphenylphosphine)palladium canbe used in this reaction. In step 2, the α-carbonyloxy ketone (31) canbe prepared by the reaction of ketone (29), prepared as described above,with an appropriate carboxylic acid (30) in the presence of lead (IV)acetate and manganese (III) acetate in the presence or absence of asolvent, but when a solvent is used, suitable solvent would be benzene,toluene and xylene. This reaction can be carried out at a temperature offrom room temperature to 150° C., preferably from 50° C. to 120° C. forfrom 10 minutes to 30 hours, more preferably from 1 hour to 15 hours.

[0324] The oxazole (Ie) can be prepared by heating the α-carbonyloxyketone (3 1) in a lower alkylcarboxylic acid such as acetic acid, formicacid and propionic acid in the presence of ammonium acetate, ammoniumformate and ammonium carbonate, preferably ammonium acetate.

[0325] Alternatively, the α-carbonyloxy ketone (31) can be prepared fromthe corresponding α-hydroxy ketone (32) or α-halo ketone (33) byreacting with an appropriate acid halide or carboxylic acid in thepresence of a base such as pyridine and triethylamine in an inertsolvent such as methylene chloride and chloroform at a temperature of−10° C. to 100° C. The corresponding α-hydroxy ketone (32) or α-haloketone (33) can be prepared by oxidation of the ketone (29) by usingiodobenzene diacetate, or by halogenation of the ketone by usingbromine, chlorine, and N-bromosuccineimide in the presence of an inertsolvent such as 1,2-dimethoxyethane, dioxane, diethyl ether,tetrahydrofuran, benzene and toluene. A compound of (Ie) wherein R² isamino can be prepared by using a compoud of (Ie) wherein R² is methyl,for example by the Huang method (Tetrahedron Lett., 1994, 35, 7201.).

[0326] The regioisomeric oxazole can be, prepared from the correspondingsulfonylbenzoic acid halide and benzyl halide.

[0327] Thiophene:

[0328] Thiophene analogs can be prepared as shown in scheme VII.

[0329] The Suzuki coupling of 2,3-dihalothiophene (VII-1) with 4-(arylor heteroaryl)phenylboronic acid, followed by the second coupling with4-(R²-thio)phenylboronic acid provides 2-[4-(aryl orheteroaryl)phenyl]-3-[4-(methylthio)phenyl]thiophene. The obtainedthiophene (VII-3) may be oxidated by the methods known in the art togive the methylsulfonyl analogs (VII-4).

[0330] Alternatively, the other arylmetal reagents such as aryl Grignardreagent, arylzinc reagent, aryltin reagent, or arylsilyl reagent insteadof arylboronic acid can be used in this reaction.

[0331] The reaction of arylbororic acid with 2,3-dihalothiophene may becarried out in a solvent such as benzene, toluene, dimethoxyethane,dimethylformamide, preferably dimethoxyethane, typically in the presenceof a base such as pottasium hydroxide, thallium hydroxide,triethylamine, sodium bicarbonate, or a combination of water and alonesolvent preferably water and dimethoxyethane. The catalyst may beselected from those typically employed for the so-called Suzuki reaction(for example, tetrakis(triphenylphosphine)palladium and dichlorobis(triphenylphosphine)palladium). The reaction is carried out at atemperature in the range from 20 to 160° C., usually 60 to 130° C. for10 minutes to 5 days, usually 30 minutes to 15 hours.

[0332] Isoxazoles:

[0333] When A is an isoxazole ring, the isoxazole derivatives (If),(Ig), and (Ig′) can be prepared from appropriate oximes (40) and (47) asshown in scheme VIII and IX.

[0334] 3,4-Diphenylisoxazoles;

[0335] Synthesis of 3,4-diphenylisoxazole is shown in scheme VIII.

[0336] In step 1, the ketone (39) can be prepared from the benzyl halide(37) and the acid halide (38), according to the procedure described instep 1 in oxazole synthesis (Scheme VI).

[0337] In step 2, the oxime (40) can be obtained by treatment of theketone (39) with hydroxylamine hydrochloride in the presence of basesuch as sodium acetate, in an inert solvent such as water, methanol,ethanol, i-propanol, tetrahydrofuran, 1,4-dioxane, diethyl ether, or amiture of the above described solvents, preferably a mixture of waterand ethanol. This reaction can be carried out at a temperature of from0° C. to reflux temperature, preferably from 50° C. to refluxtemperature for from 15 minutes to 24 hours, preferably from 1 hour to15 hours.

[0338] In step 3, the 4,5-dihydroisoxazole (41) can be prepared viaC-acylation of the oxime (40), followed by spontaneous cyclization. Thisreaction may be carried out by reacting the oxime (40) with an acylhalide, acid anhydride. N-acylimidazole, and carboxamide, in thepresence of base such as lithium amide, sodium amide, potassium amide,lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide,preferably lithium diisopropylamide, in an inert solvent such astetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dioxane, benzene,and methylene chloride, preferably diethyl ether and tetrahydrofuran, ata temperature of from −78° C. to 100° C., preferably −78° C. to roomtemperature for from 10 minutes to 30 hours, preferably from 30 minutesto 15 hours.

[0339] In step 4, the isoxazole (42) can be obtained by dehydration ofthe dihydroisoxazole (41) using acid. This may be achieved by heatingthe dihydroisoxazole (41) with acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, methanesulfonic aicd, p-toluenesulfonicacid, and polyphosphoric acid, in an inert sovlent such as methanol,ethanol, 2-propanol, tetrahydrofuran, diethyl ether, 1,4-dioxane,benznen, toluene, xylene, diglyme, dimethylforamide, dimethylsulfoxideor the like, at a temperature of from 40° C. to reflux temperature,preferably 50° C. to 100° C., for from 10 minutes to 30 hours,preferably 30 miutes to 15 hours.

[0340] In step 5, the sulfone (43a) can be prepared by oxidation of thesulfide (42a). This reaction may be carried out with an oxidant such asmCPBA, peracetic acid, hydrogen peroxide, and oxone®, in an inertsolvent such as chloroform, tetrachlorocarbon, dichloromethane, aceticacid, preferably dichloromethane, at a temperature of from −20° C. toreflux temperature, preferably 0° C. to 50° C., for from 15 minutes to30 hours, preferably 30 minutes to 15 hours. In step 6, the sulfonamide(43b) can be prepared by after reacting the isoxazole (42b) withchlorosulfonic acid at a temperature of from −78° C. to 100° C.,preferably −78° C. to 70° C., for from 15 minutes to 30 hours,preferably 30 minutes to 15 hours, pouring the reaction mixture into amixture of ice and concentrated ammonia.

[0341] In step 7, the isoxazole (If) can be obtained via the crosscoupling reaction of the isoxazole (43), as described hereinafter.

[0342] The regioisomeric isoxazole can be prepared from thecorresponding 4-methylthiobenzoyl halide and 4-bromobenzyl halide.

[0343] 4,5-Diphenylisoxazoles;

[0344] Synthesis of 4,5-diphenylisoxazole is shown in scheme IX.

[0345] In step 1, the α,β-unsaturated ketone (46) can be prepared byaldol reaction of the benzaldehyde (44) with the ketone (45), followedby β-elimination, in the presence of base, such as potassium carbonate,sodium carbonate, sodium hydride, potassium hydride, lithium amide,sodium amide, potassium amide, litium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, piperidine, and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably piperidine, in aninert solvent such as diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, benzene, toluene, xylene, and dimethylsulfoxide, preferably benzene and toulene. This reaction may be carriedout at a temperature of from −78° C. to reflux temperature, preferablyroom temperature to reflux temperature, for from 15 minutes to 50 hours,preferably 1 hour to 30 hours.

[0346] In step 2, the oxime (47) can be obtained from the ketone (46)according to the procedure described in step 2 in 3,4-diphenylisoxazolesection.

[0347] In step 3, the isoxazole (48) can be prepared by treating theoxime (47) with a mixture of iodine and potassium iodide in the presenceof base such as triethylamine, N,N-diisopropylethylamine, DBU, potassiumcarbonate, sodium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, and their aqueous solution, in an appropriatesolvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, dimethyl sulfoxide, andN,N-dimethylforamide, preferably tetrahydrofuran. This reaction may becarried out at a temperature of from 0° C. to reflux, preferably roomtemperature to reflux temperature, for from 15 minutes to 30 hours,preferably 30 minutes to 15 hours.

[0348] In step 4, the sulfone (49a) can be obtained from the sulfide(48a), according to the procedure described in step 5 in3,4-diphenylisoxazole section.

[0349] In step 5, the sulfonamide (49b) can be obtained from theisoxazole (48b), according to the procedure described in step 6 in3,4-diphenylisoxazole section.

[0350] In step 6, the isoxazoles (Ig) and (Ig′) can be respectivelyobtained from the isoxazoles (49a) abd (49b) through the cross couplingreaction described hereinafter.

[0351] Thiazole:

[0352] Thiazole can be prepared according to the following procedures ofScheme X. In step 1, the ketone (52) can be prepared by the FriedelCrafts acylation. Acid halide (50) (prferebly X═Cl or Br) is treatedwith and reacted with R²-thiobenzene (51) and lewis acid suchas-aluminum chloride, titanium(IV) chloride, and tin(IV) chloride in aninert solvent such as methylene chloride, chloroform, nitrobenzene,dichlorobenzene, chlorobenzene and carbon disulfide, at a temperature offrom 0° C. to reflux temperature, preferably from room temperature to50° C. for from 10 minutes to 30 hours, preferebly from 1 hour to 20hours. In step 2, the α-bromoketone (53) can be prepared by the reactionof ketone (52) with bromine in an inert solvent such as acetic acid,methylene chloride, chloroform, carbontetrachloride, dioxane, diethylether. This reaction can be carried out at a temperature of from roomtemperature to 150° C., preferably from 0° C. to 100° C. for from 10minutes to 30 hourrs, preferably from 1 hour to 5 hours. In step 3, thethiazole ring can be prepared by the reaction of α-bromoketone (53) withthe thioamide (54) in an inert solvent such as ethanol, methanol,dioxane, toluene, at a temperature of from 0° C. to reflux temperature,preferably from 50° C. to reflux temperature, for from 10 minutes to 30hours, preferebly 1 hour to 20 hours. In step 4, Sulfonylbenzene (Ih)can be prepared by the oxidation of sulfide compound (55). This reactionmay be carried out with an oxidizing agent such as mCPBA, peraceticacid, hydrogen peroxide and oxone®, preferably mCPBA, in an inertsolvent such as tetrachlorocarbon, dichloromethane, chloroform, andacetic acid at a temperature of from −20° C. to reflux temperature,preferably 0° C. to 50° C., for from 10 minutes to 30 hours, prefereblyfrom 1 hour to 20 hours.

[0353] The compounds of formula (1) wherein A is other than theabove-mentioned heterocyclic or carbocyclic, can be prepared accordingto the known methods.

[0354] 2) Synthesis of Compound (I) by Cross Coupling Reaction.

[0355] The compounds of formula (1) can be synthesized by using themethod of Kharash, Negishi, Stille, or Suzuki et. al., which are wellknown in the art. In general, biaryl compounds are synthesized by anumber of catalytic cross-coupling reactions from arylhalides ortriflates and arylmetal reagents, [for example, Grignard reagent (theso-called Kharasch reaction), arylzinc reagent (the so-called Negishireaction), aryltin reagent (the so-called still reaction), arylboronreagent (the so-called Suzuki reaction), arylsilyl reagent, etc. (reviewarticle showed be cited here; S. P. Stanforth, Tetrahedron, 1998, 54,263-303]. These methods can be applicable to the preparation of compound(I). The compound (I) can be prepared from corresponding aryl halides ortriflates (II) and aryl metal reagent (34), as shown in scheme XI.

[0356] (wherein X is halide or triflate, and M is boronic acid, boronicester, zinc halide, magnesium halide, or trialkyl tin groups)

[0357] The reaction of aryl or heteroarylboronic acid (34) with anarylhalide or triflate (II) may be carried out in a solvent such asbenzene, toluene, dimethoxyethane, dimethylformamide, preferablydimethoxyethane, typically in the presence of a base such as pottasiumhydroxide, thallium hydroxide, triethylamine, sodium bicarbonate, or acombination of water and alone solvent preferably water anddimethoxyethane. The catalyst may be selected from those typicallyemployed for the so-called Suzuki reaction (for example,tetrakis(triphenylphosphine)palladium and dichlorobis(triphenylphosphine)palladium). The reaction is carried out at atemperature in the range from 20 to 160° C., usually 60 to 130° C. for10 minutes to 5 days, usually 30 minutes to 15 hours.

[0358] The reaction of aryl or heteroarylzinchalide (34) with anarylhalide or triflate (II) may be carried out in a solvent such astetrahydrofuran, diethylether and dimethoxyethane, preferablytetrahydrofuran. The catalyst may be selected from those typicallyemployed for the so-called Negishi reaction (for example,tetrakis(triphenylphosphine)palladium,tetrakis(triphenylphosphine)nickel,dichlorobis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium, /n-BuLi,dichlorobis(1,1-bis(diphenylphosphino)ferrocene)palladium anddichlorobis(1,4-bis(diphenylphosphino)butane)palladium,). The reactionis carried out at a temperature in the range from 20 to 160° C., usually20 to 130° C. for 10 minutes to 5 days, usually 30 minutes to 15 hours.

[0359] The reaction of aryl or heteroaryltin reagent (34) with anarylhalide or triflate (II) may be carried out in a solvent such asdimethylformamide, tetrahydrofuran, 1,4-dioxane, benzene, toluene anddimethoxyethane, preferably tetrahydrofuran and 1,4-dioxane, ifnecessary, a salt such as lithium chloride, ammonium hydroxide,copper(I) bromide, is used. The catalyst may be selected from thosetypically employed for the so-called Stille reaction (for example,tetrakis(triphenylphosphine)palladium anddichlorobis(triphenylphosphine)palladium). The reaction is carried outat a temperature in the range from 20 to 160° C. usually 20 to 130° C.for 10 minutes to 5 days, usually 30 minutes to 15 hours.

[0360] The reaction of aryl or hetero aryl Grignard reagent (34) with anarylhalide or triflate (II) may be carried out in a solvent such astetrahydrofuran, 1,4-dioxane, benzene, toluene and dimethoxyethane,preferably tetrahydrofuran, 1,4-dioxane. The catalyst may be selectedfrom those typically employed for the so-called Kharasch reaction (forexample, dichlorobis(triphenylphosphine)nickel,dichlorobis(1,4-bis(diphenylphosphino)butane)nickel anddichlorobis(1,2-bis(diphenylphosphino)ethane)nickel,). The reaction iscarried out at a temperature in the range from 20 to 160° C., usually 20to 130° C. for 10 minutes to 5 days, usually 30 minutes to 15 hours.

[0361] As apparent to one skilled in the art, the compound (I) can beobtained from a reaction of the compound (III) or (IV), and the compound(36) as shown in scheme XII,

[0362] In step 1, the reaction of aryl halide (IT) and boron reagent(35) (G² is H or B(C₁₋₄ alkyl)₂) in an appropriate solvent such asdimethoxyethane and tetrahydrofuran in the presence of a catalyst suchas tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium and a base such as potassiumacetate, triethylamine, at heating condition (ex. 80° C. to 100° C.) for2 hours to 20 hours, gives boronic acid ester product (III).

[0363] The boronic acid ester (III) can be hydrolyzed by an acidcatalyst such as 4-toluenesulfonic acid, trifluoroacetic acid, ormineral acids (such as hydrochloric acid) in a solvent such astetrahydrofuranetoluene, diethylether, benzene, or a combination ofwater and alone solvent to form the boronic acid (IV).

[0364] The biaryl compound (1) can be prepared from boronic acid ester(III) or boronic acid (IV) and arylhalides or triflates (36) in thepresence of a catalyst such as tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium and a base such as pottasiumphosphate, triethylamine, sodium bicarbonate and sodium carbonate, atheating condition (ex., 60° C. to 150° C.) for 2 hours to 20 hours.Suitable solvents for this coupling reaction are for example benzene.,toluene, dimethoxyethane, dimethylformamide, tetrahydrofuran,1,4-dioxane, or a combination of water and alone solvent, preferablywater and dimethoxyethane. The starting material (II), wherein X ishalide or triflate can be prepared according to the methods as describedin general synthesis 1), as apparent to one skilled in the art.

[0365] The starting materials in the aforementioned general synthesesmay be obtained by conventional methods known to those skilled in theart. The preparation of such starting materials is described within theaccompanying non-limiting examples which are provided for the purpose ofillustration only. Alternatively, requisite starting materials may beobtained by analogous procedures, or modifications thereof, to thosedescribed hereinafter.

[0366] The products which are addressed in the aforementioned generalsyntheses and illustrated in the experimental examples described hereinafter may be isolated by standard methods and purification can beachieved by conventional means known to those skilled in the art, suchas distillation, crystallization or chromatography techniques.

[0367] Certain compounds described herein contain one or more asymmetriccenters and are capable of existing in various stereoisomeric forms. Thepresent invention contemplates all such possible stereoisomers as wellas their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

[0368] Certain compounds of the present invention are capable of formingaddition salts with inorganic or organic acids. The pharmaceuticallyacceptable acid salts of the compounds of formula (I) are those whichform non-toxic addition salts, such as, but not limited to, thehydrochloride, hydrobromide, sulfate or bisulfate, acetate, benzoate,besylate, citrate, fumarate, glucuronate, hippurate, lactate, tartrate,saccharate, succinate, maleate, methanesulfonate, p-toluenesulfonate,phosphate and pamoate (i.e.,4,4′-methylene-bis-(3-hydroxy-2-naphthoate)) salts. The pharmaceuticallyacceptable acid salts may be prepared by conventional techniques.

[0369] Certain compounds of the present invention are capable of formingpharmaceutically acceptable non-toxic cations. Pharmaceuticallyacceptable non-toxic cations of compounds of formula (I) may be preparedby conventional techniques by, for example, contacting said compoundwith a stoichiometric amount of an appropriate alkali or alkaline earthmetal (sodium, potassium, calcium and magnesium) hydroxide or alkoxidein water or an appropriate organic solvent such as ethanol, isopropanol,mixtures thereof, or the like.

[0370] Also included within the scope of this invention arebioprecursors (also called pro-drugs) of the compounds of the formula(I). A bioprecursor of a compound of the formula (I) is a chemicalderivative thereof which is readily converted back into the parentcompound of the formula (I) in biological systems. In particular, abioprecursor of a compound of the formula (I) is converted back to theparent compound of the formula (I) after the bioprecursor has beenadministered to, and absorbed by, a mammalian subject, e.g., a humansubject. When the compounds of the formula (I) of this invention mayform solvates such as hydrates, such solvates are included within thescope of this invention.

[0371] The compounds of the formula (I) of this invention can beadministered via either the oral, parenteral or topical routes tomammals. In general, these compounds are most desirably administered tohumans in doses ranging from 0.01 mg to 100 mg per kg of body weight perday, although variations will necessarily occur depending upon theweight, sex and condition of the subject being treated, the diseasestate being treated and the particular route of administration chosen.However, a dosage level that is in the range of from 0.1 mg to 10 mg perkg of body weight per day, single or divided dosage is most desirablyemployed in humans for the treatment of above-mentioned diseases.

[0372] The compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the above routes previously indicated, and suchadministration can be carried out in single or multiple doses. Moreparticularly, the novel therapeutic agents of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, trochees, hard candies,powders, sprays, creams, salves, suppositories, jellies, gels, pastes,lotions, ointments, aqueous suspensions, injectable solutions, elixirs,syrups, and the like. Such carriers include solid diluents or fillers,sterile aqueous media and various nontoxic organic solvents, etc.Moreover, oral pharmaceutical compositions can be suitably sweetenedand/or flavored. In general, the therapeutically-effective compounds ofthis invention are present in such dosage forms at concentration levelsranging 5% to 70% by weight, preferably 10% to 50% by weight.

[0373] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene grycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

[0374] For parenteral administration, solutions of a compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH>8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

[0375] The compounds of formula (I) may also be administered in the formof suppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

[0376] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0377] Combination with Other Drugs:

[0378] Compounds of Formula I would be useful for, but not limited to,the treatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, combinations of the invention would be useful totreat arthritis, including but not limited to rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. Such combinations of the inventionwould be useful in the treatment of asthma, bronchitis, inmenstrualcramps, tendinitis, bursitis, and skin related conditions such aspsoriasis, eczema, burns and dermatitis. Combinations of the inventionalso would be useful to treat gastrointestinal conditions such asinflammatory bowel disease. Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis and for the prevention of colorectalcancer. Combinations of the invention would be useful in creatinginflammation in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis,multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, hypersensitivity, Conjunctivitis, swellingoccurring after injury, myocardial ischemia, and the like. Thecombinations would also be useful for the treatment of certain centralnervous system disorders such as Alzheimer's disease and dimentia. Thecombinations of the invention are useful as anti-inflammatory agents,such as for the treatment of arthritis, with the additional benefit ofhaving significantly less harmful side effects. These compositions wouldalso be useful in the treatment of allergic rhinitis, respiratorydistress syndrome, endotoxin shock syndrome, atherosclerosis and centralnervous system damage resulting from stroke, ischemia and trauma.

[0379] Compounds of formula (I) will be useful as a partial or completesubstitute for conventional NSAID's in preparations wherein they arepresently co-administered with other agents or ingredients. Thus, theinvention encompasses pharmaceutical compositions for treating COX-2mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula (I) and oneor more ingredients such as another pain reliever includingacetaminophen or phenacetin; a potentiator including caffeine; anH₂-antagonist, aluminom or magnesium hydroxide, simethicone, adecongestant including phenylephrine, phenylproanolamine,psuedophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levodesoxyephedrine; an antiitussiveincluding codeine, hydrocodone, caramiphen, carbetapentane, ordextramethorphan; a prostaglandin including misoprostol, enprostil,rioprostil, omoprotol or rosaprostol; a diuretic; a sedating ornon-sedating antihistamine; anticancer agents such as angiostatin andendostatin; anti-Alzheimers such as Doepezil and Tacrine hydrochloride;and TNF alpha inhibitors such as Etanercept.

[0380] These cyclooxygenase inhibitors can further be used incombination with a nitric oxide inhibitors disclosed in WO 96/28145.

[0381] Also, the invention encompasses pharmaceutical compositions fortreating COX-2 mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula (I) and oneor more anti-ulcer agent and/or prostaglandins, which are disclosed inWO 97/11701.

[0382] The useful prostaglandins include misoprostol, plus-minus methyl11αa, 16-dihydroxy-16-methyl-9-oxoprost 13E-en-1-oate; enisoprost andmethyl-7-[2B-[6-(1-cyclopenten-1-yl)-4-hydroxy-4-methyl-1E,5E-hexadienyl]-3α-hydroxy-5-oxo 1R, 1α-cyclopentyl]-4Z-heptenoate.Prostaglandins within the scope of the invention also includearbaprostil, enprostil, rioprostol, nocloprost, mexiprostil, omoprostol,dimoxaprost, tiprostanide and rosaprostol.

[0383] The present compounds may also be used in co-therapies, partiallyor completely, in place of other conventional antiinflammatories, suchas together with steroids, 5-lipoxygenase inhibitors, LTB₄ antagonistsand LTA₄ hydrolase inhibitor's.

[0384] An example of LTB₄ is disclosed in WO97/29774. Suitable LTB₄inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigycompound CGS-25019C, Leo Denmark compound ET4-615, Lilly compoundLY-293111, Ono compound ONO-4057, Terumo compound TMK-688, Lillycompounds LY-213024, 264086 and 292728, Ono compound ONO-LB457, Searlecompound SC-S3228, calcitrol, Lilly compounds LY-210073, LY223982,LY233469, and LY255283, Ono compound ONO-LB-448, Searle compoundsSC-41930, SC-50605 and SC-51146, and SK&F compound SKF-104493.Preferably, the LTB₄ inhibitors are selected from ebselen, BayerBay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-61S, Lilly compound LY-293111, Ono compound ONO-4057 and Terumo compoundTMK-688.

[0385] An example of 5-LO inhibitors is disclosed in WO97/29776.Suitable 5-LO inhibitors include, among others, masoprocol, tenidap,zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride,enazadrem phosphate and bunaprolast.

[0386] An example of LTA₄ hydrolase inhibitors is disclosed inWO97/29774. Suitable LTA₄ hydrolase inhibitors include, among others,Rhone-Poulenc Rorer RP-4966.

[0387] The administration of the present invention may be for eitherprevention or treatment purposes. The methods and compositions usedherein may be used alone or in conjunction with additional therapiesknown to those skilled in the art in the prevention or treatment ofangiogenesis. Alternatively, the methods and compositions describedherein may be used as adjunct therapy. By way of example, thecyclooxygenase-2 inhibitor may be administered alone or in conjunctionwith other antineoplastic agents or other growth inhibiting agents orother drugs or nutrients.

[0388] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which could be selected for treatment of angiogenesis by combinationdrug chemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.Alternatively, other anti-neoplalstic agents, such as metallomatrixproteases inhibitors (MMP), such as MMP-13 inhibitors includingbatiastat, marimastat, Agouron Pharmaceuticals AG-3340, and RocheRO-32-3555, or alpha,beta,inhibitors may be used.

[0389] A first family of antineoplastic agents which may be used incombination with a selective cyclooxygenase-2 inhibitor consists ofantimetabolite-type antineoplastic agents. Suitable antimetaboliteantineoplastic agents may be selected from the group consisting of5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyly-5-fluorouracii, Daiichi Seiyaku F0-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbarnont TIF, trimetrexate, tyrosinekinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT anduricytin.

[0390] A second family of antineoplastic agents which may be used incombination with a selective cyclooxygenase-2 inhibitor consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558. Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic. Erba distamycin derivatives. Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-farn, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

[0391] A third family of antineoplastic agents which may be used incombination with a selective cyclooxygenase-2 inhibitor consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II. Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067. Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa-HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsarmicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b. Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-Ol, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887. SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B. Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-2S024 and zorubicin.

[0392] A fourth family of antineoplastic agents which may be used incombination with the selective cyclooxygenase-2 inhibitor consists of amiscellaneous family of antineoplastic agents selected from the groupconsisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston AIO, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin-glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristo-Myers BMY-40481, Vestar boron-lO, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-lOO,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate,Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, FujisawaFR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin. Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,Ionidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Nornosang. NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-IOOI, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglurnide, Invitron protease nexin I, TobishiRA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine,retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976,SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharmSP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed,SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237,Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680,taxol. Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, kyowa Hakko UCN-O1, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534.

[0393] Examples of radioprotective agents which may be used in thecombination chemotherapy of this invention are AD-5, adchnon, amifostineanalogues, detox, dimesna, 1-102, MN-159, N-acylated-dehydroalanines,TGF-Genentech, tiprotimod, amifostine, WR-151'327, FUT-187, ketoprofentransdermal, naburnetone, superoxide dismutase (Chiron) and superoxidedisrrtutase Enzon.

[0394] methods for preparation of the antineoplastic agents describedabove may be found in the literature. Methods for preparation ofdoxorubicin, for example, are described in U.S. Pat. No. 3,590,028 andNo. 4,012,448. Methods for preparing metallomatrix protease inhibitorsare described in EP 780386, WO97/20824, WO96/15096. Methods forpreparing SOD mimics are described in EP 524,1O1. Methods for preparingalpha,beta, inhibitors are described in WO97/08174.

[0395] In addition, the selective COX-2 inhibitor may be administered inconjunction with other antiinflammatory agents for maximum safety andefficacy, including NSAID's, selective COX-1 inhibitors and inhibitorsof the leukotriene pathway, including 5-lipoxygenase inhibitors.Examples of NSAID's include indomethacin, naproxen, ibruprofen,salicylic acid derivatives such as aspirin, diclofenac, ketorolac,piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium,zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulide,zaltoprofen and letodolac.

Method for Assessing Biological Activities

[0396] The activity of the compounds of the formula (I) of the presentinvention was demonstrated by the following assays.

[0397] In Vitro Assays

[0398] Human Cell Based COX-1 Assay

[0399] Human peripheral blood obtained from healthy volunteers wasdiluted to {fraction (1/10)} volume with 3.8% sodium citrate solution.The platelet-rich plasma immediately obtained was washed with 0.14 Msodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA.Platelets were then washed with platelet buffer (Hanks buffer (Ca free)containing 0.2% BSA and 20 mM Hepes). Finally, the human washedplatelets (HWP) were suspended in platelet buffer at the concentrationof 2.85×10⁸ cells/ml and stored at room temperature until use. The HWPsuspension (70 μl aliquots, final 2.0×10⁷ cells/ml) was placed in a96-well U bottom plate and 10 μl aliquots of 12.6 mM CaCl₂ added.Platelets were incubated with A23187 (final 10 μM, Sigma) with testcompound (0.1-100 μM) dissolved in DMSO (final concentration; less than0.01%) at 37° C. for 15 min. The reaction was stopped by addition ofEDTA (final 7.7 mM) and TxB2 in the supernatant quantitated by using aradioimmunoassay kit (Amersham) according to the manufacturer'sprocedure.

[0400] Human Cell Based COX-2 Assay

[0401] Inhibition of COX-2 Activity After Induction of COX-2 by hIL-1β

[0402] The human cell based COX-2 assay was carried out as previouslydescribed (Moore et al., Inflam. Res., 45, 54, 1996). Confluent humanumbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well Ubottom plate were washed with 100 μl of RPMI1640 containing 2% FCS andincubated with hIL-1β (final concentration 300 U/ml, R & D Systems) at37° C. for 24 hr. After washing, the activated HUVECs were stimulatedwith A23187 (final concentration 30 μM) in Hanks buffer containing 0.2%BSA, 20 mM Hepes and test compound (0.1 nM-100 μM) dissolved in DMSO(final concentration; less than 0.01%) at 37° C. for 15 min.6-Keto-PGFia, stable metabolite of PGI₂, in the supernatant wasquantitated after adequate dilution by using a radioimmunoassay kit(Amersham) according to the manufacturer's procedure.

[0403] Inhibition of COX-2 During the Induction Phase

[0404] Confluent human umbilical vein endothelial cells (HUVECs,Morinaga) in a 96-well U bottom plate were washed with 100 μl of RPM]1640 containing 2% FCS and test compound (0.1 nM-100 μM) dissolved inDMSO (final concentration; less than 0.01%), and incubated with hIL-10(final concentration 300 U/ml, R & D Systems) at 37° C. for 24 hr. Afterwashing, the HUVECs were stimulated with A23187 (final concentration 30μM) in Hanks buffer containing 0.2% BSA and 20 mM Hepes at 37° C. for 15min. 6-Keto-PGF_(1α), a stable metabolite of PGI₂, in the supernatantwas quantitated after adequate dilution by using a radioimmunoassay kit(Amersham) according to the manufacturer's procedure.

[0405] In Vivo Assays

[0406] Carrageenan Induced Foot Edema in Rats

[0407] male Sprague-Dawley rats (5 weeks old, Charles River Japan) werefasted overnight. A line was drawn using a marker above the ankle on theright hind paw and the paw volume (V0) was measured by waterdisplacement using a plethysmometer (Muromachi). Animals were givenorally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a testcompound (2.5 ml per 100 g body weight). One hour later, the animalswere then injected intradermally with λ-carrageenan (0.1 ml of 1% w/vsuspension in saline, Zushikagaku) into right hind paw (Winter et al.,Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim.Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3) wasmeasured and the increase in volume (V3-V0) calculated. Since maximuminhibition attainable with classical NSAIDs is 60-70%, ED₃₀ values werecalculated.

[0408] Gastric Ulceration in Rats

[0409] The gastric ulcerogenicity of test compound was assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29,330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles RiverJapan), fasted overnight, were given orally either vehicle (0.1% methylcellulose or 5% Tween 80) or a test compound (1 ml per 100 g bodyweight). Six hours after, the animals were sacrificed by cervicaldislocation. The stomachs were removed and inflated with 1% formalinsolution (10 ml). Stomachs were opened by cutting along the greatercurvature. From the number of rats that showed at least one gastriculcer or haemorrhaging erosion (including ecchymosis), the incidence ofulceration was calculated. Animals did not have access to either food orwater during the experiment.

[0410] Data Analysis

[0411] Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView(Abacus Cencepts, Inc.) for Macintosh were used. Differences betweentest compound treated group and control group were tested for usingANOVA. The IC₅₀ (ED₃₀) values were calculated from the equation for thelog-linear regression line of concentration (dose) versus percentinhibition.

[0412] most compounds prepared in the Working Examples as describedherein after were tested by these methods, and showed IC₅₀ values of0.001 μM to 3 μM with respect to inhibition of COX-2.

[0413] COX-2 selectivity can be determined by ratio in terms of IC₅₀value of COX-1 inhibition to COX-2 inhibition. In general, it can besaid that a compound showing a COX-2/COX-1 inhibition ratio of more than2 has good COX-2 selectivity.

[0414] Some compounds prepared in Examples showed COX-2/COX-1 inhibitionratio of more than 5.

[0415] The following examples contain detailed descriptions of themethods of the preparation of compounds of formula (I). These detaileddescriptions fall within the scope of the invention and serve toexemplify the above described general synthetic procedures which formpart of the invention. These detailed descriptions are presented forillustrative purposes only and are not intended to restrict the scope ofthe present invention.

EXAMPLES

[0416] The invention is illustrated in the following non-limitingexamples in which, unless stated otherwise: all operations were carriedout at room or ambient temperature, that is, in the range of 18-25° C.;evaporation of solvent was carried out using a rotary evaporator underreduced pressure with a bath of up to 60° C.; reactions were monitoredby thin layer chromatography (tlc) and reaction times are given forillustration only; melting points (m.p.) given are uncorrected(polymorphism may result in different melting points); structure andpurity of all isolated-compounds were assured by at least one of thefollowing techniques: tic (Merck silica gel 60 F-254 precoated plates),mass spectrometry, nuclear magnetic resonance (NMR) or infraredspectroscopy (IR). IR data were obtained on a FTR 8200 (SHIMAZUSpectrometer). Yields are given for illustrative purposes only. Flashcolumn chromatography was carried out using Merck silica gel 60 (230400mesh ASTM). Low-resolution mass spectral data (EI) were obtained on aAutomass 120 (JEOL) mass spectrometer. NMR data was determined at 270MHz (JEOL JNM-LA 270 spectrometer) using deuterated chloroform (99.8%D), methanol (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unlessindicated otherwise, relative to tetramethylsilane (TMS) as internalstandard in parts per million (ppm); conventional abbreviations usedare: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad,etc.

[0417] The following abbrevation are used: THF: tetrahydrofuran CH₂Cl₂:dichloromethane NaHCO₃: sodium bicarbonate HCl: hydrogen chloride MgSO₄:magnesium sulfate Na₂SO₄: sodium sulfate DME: dimethoxyethane n-BuLi:n-butyllithium DMF: dimethylformamide

Example 1

[0418]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-trifluoromethyl-1H-pyrrazole

[0419]1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-]H-pyrrazole (Step 1)

[0420] (4-methylsulfonylphenyl)hydrazine hydrochloride (commerciallyavailable from Fisher Scientific USA) (0.83 g, 3.7 mmol) was added to asolution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1 g. 3.39mmol), prepared according to the method of J. Med. Chem. 1997, 40, 1347)in EtOH (15 mL). The mixture was heated at reflux temperature for 20hours and cooled down to room temperature. The reaction mixture wasconcentrated in vacuo, and the residue was taken up in ethyl acetate,washed with water and brine, dried over sodium sulfate, and concentratedin vacuo. The residue was purified by flash chromatography eluting withhexane/ethyl acetate (1/1) to give the title compound (1.08 g).

[0421]¹H-NMR (CDCl₃) δ: 7.97 (ddd, J=9, 2, 2 Hz, 2H), 7.50-7.57 (m, 4H),7.11 (ddd, J=9, 2, 2 Hz, 2H), 6.79 (s, 1H), 3.08 (s, 3H).

[0422]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-trifluoromethyl-1H-pyrrazole,(Step 2)

[0423] To a stirred solution of1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrrazole.(0.27 g, 0.6 mmol) in DME (8 mL) was added 3-thiophenboronic acid (0.09g, 0.7 mmol), bis(triphenylphosphine)palladium(II)chloride (0.05 g, 0.1mmol) and saturated NaHCO₃ solution (2 mL) at room temperature undernitrogen. The mixture was heated at reflux temperature for 16 hours, andcooled down to room temperature. The reaction mixture was purified byflash chromatography eluting with ethyl acetate/hexane (1/1). Theresulting solid was recrystallized with dichloroethane-hexane to givetitle compound (0.171 g, 64% yield).

[0424] mp: 191-192° C.

[0425]¹H-NMR (CDCl₃) δ: 7.96 (ddd, J=9, 2, 2 Hz, 2H), 7.63 (ddd, J=9, 2,2 Hz, 2H), 7.58 (ddd, J=9, 2, 2 Hz, 2H), 7.38 (dd, J=4, 1 Hz, 1H), 7.34(dd, J=5, 1 Hz, 1H), 7.24 (ddd, J=9, 2, 2 Hz, 2H), 7.11 (dd, J=5, 4 Hz,1H), 6.82 (s, 1H), 3.70 (s, 3H).

[0426] Anal. Calcd. for C₂₁H₁₅N₂O₂F₃S: C, 56.24; H, 3.37; N, 6.25.Found: C, 55.84; H, 3.49; N, 6.07.

Example 2

[0427]1-4-(Methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-trifluoromethl)-1H-pyrazole

[0428] The title compound was prepared according to the procedure ofExample 1 (Step 2) using 3-thienylboronic acid, instead of2-thienyboronic acid.

[0429] mp: 153.5-155° C.

[0430]¹H-NMR (CDCl₃) δ: 7.96 (ddd, J=9, 2, 2 Hz, 2H), 7.62 (ddd, J=9, 2,2 Hz, 2H), 7.58 (ddd, J=9, 2, 2 Hz, 2H), 7.53 (dd, J=3, 1 Hz, 1H),7.45-7.38 (m, 2H), 7.28-7.24 (m, 2H), 6.82 (s, 1H), 3.07 (s, 3H).

[0431] Anal. Calcd. for C₂₁H₁₅N₂O₂F₃S₂: C, 56.24; H, 3.37; N, 6.25.Found: C, 56.14; H. 3.40; N, 6.27.

Example 3

[0432]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-trifuoromethyl-1H-pyrazole

[0433] The title compound was prepared according to the procedure ofExample 1 (Step 2) using 2-furylboronic acid, instead of2-thienylboronic acid.

[0434] mp: 195.5-196.5° C.

[0435]¹H-NMR (CDCl₃) δ: 7.95 (ddd, J=9, 2, 2 Hz, 2H), 7.68 (ddd, J=9,2.2 Hz, 2H), 7.57 (ddd, J=9, 2, 2 Hz, 2H), 7.51 (dd, J=2, 1 Hz, 1H),7.26-7.22 (m, 2H), 6.81 (s, 1H), 6.74 (dd, J=4, 1 Hz, 1H), 6.51 (dd,J=4, 2 Hz, 1H), 3.07 (s, 3H).

[0436] Anal. Calcd. for C₂₁H₁₅N₂O₃F₃S ¼H₂O: C, 57.73; H, 3.58; N, 6.41.Found: C, 57.89; H, 3.54; N, 6.30.

Example 4

[0437]1-[4-(Methylsulfonyl)phenyl]-5-[4-(benzo[b]furan-2-yl)phenyl]-3-trifluoromethyl-1H-pyrazole

[0438] The title compound was prepared according to the procedure ofExample 1 (Step 2) using 2-benzo[b]furylboronic acid, instead of2-thienylboronic acid.

[0439] mp: 137-138° C.

[0440]¹H-NMR (CDCl₃) δ: 7.98 (ddd, J=9, 2, 2 Hz, 2H), 7.88 (ddd, J=9, 2,2 Hz, 2H), 7.63-7.51 (m, 4H), 7.36-7.25 (m, 4H), 7.10 (d, J=1 Hz, 1H),6.85 (s, 1H), 3.08 (s, 3H).

[0441] Anal. Calcd. for C₂₅H₁₇N₂O₃F₃S ¼H₂O: C, 61.66H, 3.62; N, 5.75.Found: C, 61.72; H, 3.95; N, 5.42.

Example 5

[0442]4-[5-[4-(3-Thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0443]4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 1)

[0444] 4-sulphonamidophenylhydrazine hydrochloride (commerciallyavailable from Maybridge Chemical Company ltd.) (7.38 g, 33 mmol) wasadded to a solution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione(8.85 g, 30 mmol, prepared according to the method of J. Med. Chem.,1997, 40, 1347) in EtOH (120 mL). The mixture was heated at refluxtemperature for 20 hours and cooled down to room temperature. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby recrystellized with diisopropyl ether, to give the title compound(9.1 g).

[0445]¹H-NMR (CDCl₃) δ: 7.94 (d, J=8 Hz. 2H), 7.45-7.55 (m, 4H), 7.11(d, J=8 Hz, 2H), 6.78 (s, 1H), 4.93 (br, 2H).

[0446]4-[5-[4-(3-Thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide,(Step 2)

[0447] To a stirred solution of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.22 g, 0.50 mmol) in DME (6 mL) was added thiophen-3-boronic acid(0.08 g, 0.6 mmol), bis(triphenylphosphine)palladium(II)chloride (0.05g, 0.1 mmol) and saturated NaHCO₃ solution (2 mL) at room temperatureunder nitrogen. The mixture was heated at reflux temperature for 16hours, and cooled down to room temperature. The reaction mixture waspurified by flash chromatography eluting with ethyl acetate/hexane(1:5). The resulting solid was recrystallized with CH₂Cl₂-hexane to givetitle compound (0.090 g, 40% yield).

[0448] mp: 205-207° C.

[0449]¹H-NMR (DMSO d₆) δ: 8.00-7.98 (m. 1H), 7.90 (d, J=8 Hz, 2H), 7.79(d, J=8 Hz, 2H), 7.67-7.58 (m, 4H), 7.52 (s, 2H), 7.36 (d, J=8 Hz, 2H),7.29 (s, 1H).

[0450] Anal. Calcd. for C₂₀H₁₄N₃O₂F₃S₂: C, 53.44; H, 3.14; N, 9.35.Found: C, 53.13; H, 3.40; N, 9.06.

Example 6

[0451]4-[5-[4-(3-thienyl)phenyl]-4-cyano-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0452] The title compound was prepared according to the procedure ofExample 5 using4-[5-[4-Bromophenyl]-4-cyano-1H-pyrazol-1-yl]-1-phenylsulfonamide,instead of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide.

[0453] mp: 201.5-202° C.

[0454]¹H-NMR (CDCl₃) δ: 8.07 (s, 1H), 7.95 (ddd, J=9, 2, 2 Hz, 2H), 7.67(ddd, J=8, 2, 2 Hz, 2H), 7.55 (dd, J=3, 1 Hz, 1H), 7.49 (ddd, J=9, 2, 2Hz, 2H), 7.45-7.39 (m, 2H), 7.36 (ddd, J=8, 2, 2 Hz, 2H), 4.87 br, 2H).

[0455] Anal. Calcd. for C₂₀H₁₄N₄O₂S₂ ½H₂O: C, 57.82; H, 3.64; N, 13.48.Found: C, 57.47; H, 3.68; N, 13.13.

Example 7

[0456]4-[5-[4-(4-Pyridyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0457] The title compound was prepared according to the procedure ofExample 5 using 4-pyridylboronic acid, instead of 3-thienylboronic acid.

[0458] mp: 164-166° C.

[0459]¹H-NMR (DMSO d₆) δ: 8.64 (d, J=6 Hz, 2H), 7.91 (d. J=9 Hz, 2H),7.88 (d, J=8 Hz, 2H), 7.75 (d, J=6 Hz, 2H), 7.61 (d J=9 Hz, 2H). 7.50(d, J=6 Hz, 2H), 7.47 (s, 2H), 7.32 (s, 1H).

[0460] Anal. Calcd. for C₂₁H₁₅F₃N₄O₂S ¼H₂O: C, 56.18H, 3.48; N, 12.48.Found: C, 56.07; H, 3.56; N, 12.10.

Example 8

[0461]4-[5-[4-(3-Pyridyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide

[0462] The title compound was prepared according to the procedure ofExample 5 using 3-pyridylboronic acid, instead of 3-thienylboronic acid.

[0463] mp: 138-140° C.

[0464]¹H-NMR (CDCl₃) δ: 8.52 (d, J=5 Hz, 1H), 8.78 (s, 1H), 7.88 (d, J=8Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 7.38-7.30 (m. 4H).6.81 (s, 1H), 6.30 (s, 2H).

[0465] Anal. Calcd. for C₂₁H₁₅F₃N₄O₂S {fraction (1/10)}H₂O: C, 56.52H,3.43; N, 12.56. Found: C, 56.86; H, 3.83; N, 12.30.

Example 9

[0466]4-[5-[4-(5-Methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0467] 5-Methyl-2-thienylboronic acid (Step 1)

[0468] To a stirred soluition of 2-bromo-5-methylthiophene (2.5 g, 14.1mmol) in THF (30 mL) was added n-BuLi (1.55 M solution in hexane, 10.0mL, 15.5 mmol) at −78° C. under nitrogen, and the mixture was stirredfor 1 hour. Trimethylborate (1.83 g, 17.6 mmol) was added to themixture, and residue was allowed to warm up to room temperatureovernight. The reaction mixture was cooled at 0° c and 2N HCl (10 mL)was added, and the mixture was stirred for 1 hour. The organic layer wasseparated and the aqueous layer was extracted with diethylether. Thecombined organic layer was washed with brine, dried over MgSO₄, andconcetrated in vacuo, to give the title compound (1.36 g).

[0469]¹H-NMR (DMSO d₆) δ: 7.45 (s, 2H), 7.09 (d, J=3 Hz, 1H), 6.88 (d,J=3 Hz. 1H). 1.88 (s, 3H).

[0470]4-[5-[4-(5-Methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0471] The title compound was prepared according to the procedure ofExample 5 using 5-methyl-2-thienylboronic acid, instead of3-thienylboronic acid.

[0472] mp: 218-220° C.

[0473]¹H-NMR (DMSO d₆) δ: 7.90 (d, J=9 Hz, 2H), 7.63 (d, J=7 Hz, 2H),7.58 (d, J=7 Hz, 2H), 7.52 (s, 2H), 7.40 (d, J=4 Hz, 1H), 7.32 (d, J=9Hz, 2H), 7.27 (s, 1H), 6.84 (dd, J=4, 1 Hz, 1H), 2.47 (s, 3H).

[0474] Anal. Calcd. for C₂₁H₁₆F₃N₃O₂S₂: C, 54.42H, 3.48; N, 9.07. Found:C, 54.43; H, 3.67; N, 8.91.

Example 10

[0475]4-[5-[4-(3-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0476] The title compound was prepared according to the procedure ofExample 5 using 3-furylboronic acid (prepared according to the method ofJ. Org. Chem., 1984, 26, 5241.), instead of 3-thienylboronic acid.

[0477] mp: 163-165° C.

[0478]¹H-NMR (CDCl₃) δ: 7.93 (d, J=9 Hz, 2H), 7.79-7.74 (m, 1H),7.54-7.47 (m, 5H), 7.23 (d, J=8 Hz, 2H), 6.79 (s, 1H), 6.72-6.68 (m,1H), 4.90 (s, 2H).

[0479] Anal. Calcd. for C₂₀H₁₄N₃O₃F₃S: C, 55.43; H, 3.26; N, 9.70.Found: C, 55.25; H, 3.30; N, 9.64.

Example 11

[0480]4-[5-[4-(5-Pyrimidinyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0481] The title compound was prepared according to the procedure ofExample 5 using 5-pyrimidinylboronic acid, instead of 3-thienylboronicacid.

[0482] mp: 220-222° C.

[0483]¹H-NMR (DMSO d₆), δ: 9.20 (d, J=4 Hz, 2H), 7.91 (d, J=8 Hz, 2H),7.64-7.49 (m, 9H), 7.35 (s, 1H).

[0484] Anal. Calcd. for C₂₀H₁₄F₃N₅O₂S ½H₂O: C, 52.86; H, 3.33; N, 15.41.Found: C, 52.91; H, 3.24; N, 15.06.

Example 12

[0485]4-[5-[4-(2-Pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0486] The title compound was prepared according to the procedure ofExample 5 using (1-tert-butoxycarbonylpyrrol-2yl)boronic acid (preparedaccording to the method of Synthesis, 613 (1991)), instead of3-thienylboronic acid.

[0487] mp: 263-265° C.

[0488]¹H-NMR (DMSO d₆) δ: 11.0 (brs, 1H), 7.89 (d, J=8 Hz. 2H),7.60-7.55 (m, 4H), 7.50 (s, 2H), 7.31 (s, 1H), 7.24-7.21 (m, 3H), 6.80(s, 1H), 6.48 (s, 1H).

[0489] Anal. Calcd. for C₂₀H₁₅F₃N₄O₂S 0.3H₂O: C, 54.87; H, 3.59; N,12.80. Found: C, 54.63; H, 3.65; N, 12.59.

Example 13

[0490]4-[5-[4-(2-Benzothienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0491] The title compound was prepared according to the procedure ofExample 5 using 2-benzothienyl-boronic acid, instead of 3-thienylboronicacid.

[0492] mp: 223-225° C.

[0493]¹H-NMR (DMSO d₆) δ: 8.00-7.82 (m, 7H), 7.62 (d, J=9 Hz, 2H), 7.54(s, 2H); 7.45-7.37 (m, 4H), 7.33 (s, 1H).

[0494] Anal. Calcd. for C₂₄H₁₆F₃N₃O₂S₂H₂O: C, 57.71; H, 3.23; N, 8.41.Found: C, 57.45; H, 3.36; N, 8.36.

Example 14

[0495]4-[5-[4-(5-Acelylthiophene-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0496] The title compound was prepared according to the procedure ofExample 5 using 5-acetyl-2-thienylboronic acid, instead of3-thienylboronic acid.

[0497] mp: 212-214° C.

[0498]¹H-NMR (DMSO d₆) δ: 7.95 (d, J=4 Hz, 1H), 7.91 (d, J=8 Hz, 2H),7.83 (d, J=8 Hz, 2H), 7.73 (d, J=4 Hz, 1H), 7.60 (d, J=8 Hz, 2H), 7.51(s, 2H), 7.41 (d, J=8 Hz, 2H), 7.31 (s, 1H), 2.25 (s, 3H).

[0499] Anal. Calcd. for C₂₂H₁₆F₃N₃O₃S₂ {fraction (1/10)}H₂O: C, 53.56;H, 3.31; N, 8.52. Found: C, 53.25; H, 3.40; N, 8.35.

Example 15

[0500]4-[5-[4-(3-Pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0501]4-[5-[4-(]-Triisopropylsilylpyrrol-3-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 1)

[0502] The title compound was prepared according to the procedure ofExample 5 using 1-(triisopropylsilyl)pyrrole-3-boronic acid (preparedaccording to the method of Alejandro Alvarez et. al., J. Org. Chem.,1992, 57, 1653.), instead of 3-thenylboronic acid.

[0503]4-[5-[4-(3-Pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0504] To a stirred solution of4-[5-[4-(1-triisopropylsilylpyrrol-3-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.50 g, 0.849 mmol) in THF (13 mL) was added tetrabutylammoniumfluoride (1.00 M solution in THF, 0.85 mL, 0.85 mmol) at roomtemperature under nitrogen, and the mixture was stirred for 5 minutes.The solvent was removed in vacuo. The residue was purified by flashchromatography eluting with CH₂Cl₂-methanol (20:1). The resulting solidwas recrystallized with CH₂Cl₂-hexane to give the title compound (0.070g, 30% overall yield).

[0505] mp: 262-264° C.

[0506]¹H-NMR (DMSO d₆) δ: 11.0 (s, 1H), 7.90 (d, J=9 Hz, 2H), 7.57 (d,J=9 Hz, 4H), 7.49 (s, 2H), 7.28 (s, 1H), 7.21 (d, J=9 Hz, 2H), 7.15 (s,1H), 6.79 (d, J=2 Hz, 1H), 6.47 (d, J=2 Hz, 1H).

[0507] Anal. Calcd. for C₂₀H₁₅F₃N₄O₂S: C, 55.55; H, 3.50; N, 12.96.Found: C, 55.21; H, 3.68; N, 12.85.

Example 16

[0508]4-[5-[4-(3-Methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0509] 3-Methyl-2-thienylboronic acid (Step 1)

[0510] The title compound was prepared according to the procedure ofExample 9 using 2-bromo-3-methylthiophene.

[0511]4-[5-[4-(3-Methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0512] The title compound was prepared according to the procedure ofExample 5 using 3-methyl-2-thienylboronic acid, instead of3-thienylboronic acid.

[0513] mp: 164-166° C.

[0514]¹H-NMR (CDCl₃) δ 7.95 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.49(d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 7.25 (d, J=5 Hz, 1H), 6.94 (d,J=5 Hz, 1H), 6.81 (s, 1H), 4.91 (s, 2H), 2.35 (s, 3H).

[0515] Anal. Calcd. for C₂₁H₁₆F₃N₃O₂S₂ ½H₂O: C, 53.38; H, 3.63; N. 8.89.Found: C, 53.42; H, 3.74; N, 8.92.

Example 17

[0516] Methyl1-[4-(sulfamoylphenyl]-5-[4-(3-thienyl)phenyl]-1H-pyrrazole-3-carboxylate

[0517] Methyl1-[4-sulfamoylphenyl]-5-(4-bromophenyl)-1H-pyrrazole-3-carboxylate.(Step 1)

[0518] The subtitle compound was prepared according to the procedure ofExample 5 using methyl 4-(4-bromophenyl)-2,4-diketobutyrate (preparedaccording to the method of J. Med. Chem., 1997, 40, 1347) instead of4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione in step 1.

[0519]¹H-NMR (CDCl₃) δ: 7.93 (ddd, J=9, 2, 2 Hz, 2H), 7.54-7.53 (m, 4H),7.10 (ddd, J=8, 2, 2 Hz, 2H), 7.06 (s, 1H), 4.88 (br, 2H), 3.99 (s, 3H).

[0520] Methyl1-[4-(sulfamoylphenyl)-5-[4-(3-thienyl)phenyl]-]H-pyrrazole-3-carboxylate.(Step 2)

[0521] To a stirred solution of Methyl1-[4-(sulfamoylphenyl]-5-(4-bromophenyl)-1H-pyrrazole-3-carboxylate.(0.28 g, 0.65 mmol) in DMF (3 mL) was addedbis(triphenylphosphine)palladium(II)chloride (0.02 g, 0.03 mmol),3-thiophenboronic acid (0.09 g, 0.7 mmol) and triethylamine (0.2 g; 1.95mmol) at room temperature under nitrogen. The mixture was heated at 100°C. for 3 hours, and cooled down to room temperature. The reactionmixture was purified by flash chromatography eluting with ethylacetate/hexane (2/1). The resulting solid was recrystallized withdichloroethane-hexane to give title compound (0.15 g, 53% yield).

[0522] mp: 138-140° C.

[0523]¹H-NMR (CDCl₃) δ: 7.92 (d, J=9 Hz, 2H), 7.6 (d, J=9 Hz, 2H),7.5-7.49 (m, 3H), 7.44-7.38 (m, 2H), 7.26-7.23 (2H), 7.08 (s, 1H), 4.90(s, 2H), 3.99 (s, 3H).

Example 18

[0524]4-[3-(Cyanomethyl)-5-[4-(3-thienyl)phenyll]-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0525]4-[3-(Hydroxymethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-1-phenylsulfonamide.(Step l)

[0526] To a stirred suspention of lithium alminium hydride (0.278 g,7.33 mmol) in THF (50 ml) was added a solution of Methyl1-[4-sulfamoylphenyl]-5-(4-bromophenyl)-1H-pyrrazole-3-carboxylate (4.0g, 9.17 mmol) (EXAMPLE 17 step 1) in THF (80 ml). Resulting mixture wasstirred continured for 1 hour at reflux temperature, and cooled down toroom temperature. A suspention of lithium alminium hydride (0.07 g) inTHF (1 ml) was added to the reaction mixture and the whole was heated atreflux temperature for 1 hour, then cooled to room temperature. Water(10 ml) was added to the reaction mixture and the resulting mixture wasacidified with 20% H₂SO₄ solution.

[0527] The whole was extracted with ethyl acetate and organic layer waswashed with water and brine, dried over magesium sulfate, andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with ethyl acetate/hexane (1/2) to give the title compound (2.9g).

[0528]¹H-NMR (CD₃OD) δ: 7.90 (ddd, J=9, 2, 2 Hz, 2H), 7.51 (ddd, J=9, 2,2 Hz, 2H), 7.42 (ddd, J=9, 2, 2 Hz, 2H), 7.17 (ddd, J=9, 2, 2 Hz, 2H),6.65 (s, 1H), 4.67 (s, 2H).

[0529]4-[3-(Chloromethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-phenylsulfonamide,(Step 2)

[0530] To a stirred mixture of4-[3-(Hydroxymethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-phenylsulfonamide(1.67 g, 4.1 mmol), p-toluenesulphonic acid (0.78 g, 4.1 mmol), lithiumchloride (0.18 g, 4.1 mmol), triethylamine (0.415 g, 4.1 mmol) and THF(60 ml) was heated at reflux temperature for 20 hours, and cooled downto room temperature. The reaction mixture was taken up in ethyl acetate,washed with 1N—HCl solution, sat-NaHCO3 solution and brine, dried overmagesium sulfate, and concentrated in vacuo. The residue was purified byflash chromatography eluting with ethyl acetate/hexane (1/1) to give thetitle compound (0.62 g).

[0531]¹H-NMR (DMSO d6) δ: 7.85 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H),7.44-7.48 (m, 4H), 7.23 (d, J=8 Hz, 2H), 6.82 (s, 1H), 4.82 (s, 2H).4-[3-(Cyanomethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-phenylsulfonamide.(Step 3)

[0532] To a stirred solution of sodium cyanide (0.084 g, 1.7 mmol) inDMSO (10 ml) was added a solution of4-[3-(Chloromethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.61 g, 1.43 mmol) in DMSO (10 ml). Resulting mixture was stirredcontinured for 4 hours at 100° C., and cooled down to room temperature.The reaction mixture was taken up in ethyl acetate, washed with waterand brine, dried over magesium sulfate, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethyl acetateto give the title compound (0.46 g).

[0533]¹H-NMR (DMSO d6) o: 7.85 (d, J=9 Hz. 2H), 7.62 (d, J=9 Hz. 2H),7.44-7.48 (m, 4H). 7.23 (d, J=9 Hz. 2H), 6.74 (s, 1H), 4.15 (s, 2H).

[0534]4-[3-(Cyanomethyl)-5-[4-(3-thienyl)phenyll]-1H-pyrazol-1-yl]-1-phenylsulfonamide.(Step 4)

[0535] The title compound was prepared according to the procedure ofExample 17 using4-[3-(Cyanomethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-phenylsulfonamide.

[0536] mp: 211-212° C.

[0537]¹H-NMR (CDCl₃) δ: 7.95 (ddd, J=9, 2, 2 Hz, 2H), 7.68 (ddd, J=9, 2,2 Hz, 2H), 7.57 (ddd, J=9, 2, 2 Hz, 2H), 7.51 (dd, J=2, 1 Hz, 1H),7.26-7.22 (m, 2H), 6.81 (s, 1H), 6.74 (dd, J=4, 1 Hz, 1H), 6.51 (dd,J=4, 2 Hz, 1H), 3.07 (s, 3H).

[0538] Anal. Calcd. for C₂₁H₁₅N₂O₃F₃S ¼H₂O: C, 57.73; H, 3.58; N, 641.Found: C, 57.89; H, 3.54; N, 6.30.

Example 19

[0539]4-[3-(Hydroxymethyl)-5-[4-(3-thienyl)phenyl]-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0540] The title compound was prepared according to the procedure ofExample 17 using4-[5-(4-Bromophenyll)-3-(hydroxymethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide.

[0541] mp: 228-229° C.

[0542]¹H-NMR (CD₃OD) δ: 7.96 (dd, J=3, 2 Hz, 1H), 7.83 (d, J=9 Hz, 2H),7.77 (d, J=9 Hz, 2H), 7.66 (dd, J=5, 3 Hz, 1H), 7.60 (dd, J=5, 2 Hz,1H), 7.47-7.44 (m, 4H), 7.29 (d, J=9 Hz, 2H), 6.68 (s, 1H), 5.26 (t, J=6Hz, 1H), 4.53 (d, J=6 Hz, 2H).

[0543] Anal. Calcd. for C₂₀H₁₇N₃O₃S₂ ¼H₂O: C, 57.74; H. 4.24; N, 10.10.Found: C, 57.83; H, 4.27; N, 10.01.

Example 20

[0544]1-[4-(Methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[0545] The title compound was prepared according to the procedure ofExample 17 using1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazoleand furan-3-boronic acid, instead of thiophen-3-boronic acid.

[0546] mp: 165-166° C.

[0547]¹H-NMR (CDCl₃) δ: 7.96 (ddd, J=9, 2, 2 Hz, 2H), 7.79 (br, 1H),7.57 (ddd, J=9, 2, 2 Hz, 2H), 7.52-7.48 (m, 3H), 7.26-7.22 (m, 2H), 6.81(s, 1H), 6.71 (br, 1H), 3.07 (s, 3H). Anal. Calcd. for C₂₁H₁₅N₂O₃F₃S½H₂O: C, 57.14; H, 3.65; N, 6.35. Found: C, 57.48; H, 3.61; N, 6.34.

Example 21

[0548]4-[5-[4-(2-Thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0549] To a stirred solution of thiazole (1.61 g, 18.9 mmol) indiethylether (20 mL) was added n-BuLi (1.58 M solution in hexane, 12.7mL, 20.0 mmol) at −78° C. under nitrogen, and the mixture was stirredfor 30 minutes. Zinc chloride (1.0 M solution in diethylether, 20 mL, 20mmol) was added, and the mixture was allowed to warm up to roomtemperature for 30 minutes.4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.60 g, 1.34 mmol), tetrakis(triphenylphosphine)palladium (0.02 g,0.173 mmol) was added, and the mixture was heated at reflux temperaturefor 5 hours, and cooled down to room temperature. The mixture wasfiltered through celite, and the filterate was washed with brine, driedover MgSO₄, concentrated in vacuo. The residue was purified by flashchromatography eluting with ethyl acetate/hexane (1/2). The resultingsolid was recrystallized with CH₂Cl₂-hexane to give the title compound(0.155 g; 26% yield).

[0550] mp: 120-122° C.

[0551]¹H-NMR (CDCl₃) δ: 7.99 (d, J=8 Hz, 2H), 7.93 (d, J=9 Hz. 2H), 7.90(d, J=3 Hz, 1H), 7.50 (d, J=9 Hz, 2H), 7.40 (d, J=3 Hz, 1H), 7.32 (d,J=8 Hz, 2H), 6.85 (s, 1H), 5.00 (s, 2H).

[0552] Anal. Calcd. for C₁₉H₁₃F₃N₄O₂S₂H₂O: C, 48.71; H, 3.23; N, 11.96.Found: C, 48.78; H, 3.00; N, 11.98.

Example 22

[0553]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[0554] The title compound was prepared according to the procedure ofExample 21 using1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.

[0555] mp: 206-207° C.

[0556]¹H-NMR (CDCl₃) δ: 8.01-7.94 (m, 4H), 7.91 (d, J=3 Hz, 1H), 7.57(ddd, J=9, 2, 2 Hz, 2H), 7.41 (d, J=3 Hz, 1H), 7.33 (ddd, J=9, 2.2 Hz,2H), 6.86 (s, 1H), 3.08 (s, 3H). Anal. Calcd. for C₂₀H₁₄N₃O₂F₃S₂: C,53.44; H, 3.14; N, 9.35. Found: C, 53.20; H, 3.33; N, 9.14.

Example 23

[0557]4-[5-[4-(5-Thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0558] 2-Trimethylsilyl-5-trimethylstannylthiazole (Step 1)

[0559] To a stirred solution of n-BuLi (1.61 M solution in hexane, 9.3mL, 15.0 mmol) in diethylether (60 mL) was added a solution of2-trimethylsilylthiazole (1.97 g, 12.5 mmol) in diethylether (25 mL)dropwise at −78° C. over 1 hour under nitrogen. The mixture was stirredat −78° C. for 1 hour, and then a solution of 2-trimethyltinchloride(3.00 g, 15.0 mmol) in diethylether (20 mL) was added dropwise over 20minutes. After an additional 3 hours at −78° C., the reaction mixturewas filtered and the filterate was concentrated in vacuo to give 4.17 gof creem colored solid. The compound was used for next reaction withoutpurification.

[0560]4-[5-[4-(5-Thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0561] To a stirred solution of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.30 g, 0.67 mmol) in benzene (8 mL) was added2-trimethylsilyl-5-trimethylstannylthiazole (0.26 g, 0.8 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.087 mmol) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 40 hours, and cooled down to room temperature. The reaction mixturewas purified by flash chromatography eluting with ethyl acetate/hexane(1/2). The resulting solid was recrystallized with CH₂Cl₂-hexane to givetitle compound (0.170 g, 56% yield).

[0562] mp: 222-224° C.

[0563]¹H-NMR (DMSO d₆) δ: 9.13 (s, 1H), 8.41 (s, 1H), 7.90 (d, J=8 Hz,2H), 7.76 (d, J=8 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 7.52 (s, 2H), 7.40 (d,J=8 Hz, 2H), 7.32 (s, 1H).

[0564] Anal. Calcd. for C₁₉H₁₃F₃N₄O₂S₂ ¼H₂O: C, 50.16; H, 2.99; N,12.31. Found: C, 49.93; H, 3.20; N, 12.26.

Example 24

[0565]1-[4-(Methylsulfonyl)phenyl]-5-[4-(5-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[0566] The title compound was prepared according to the procedure ofExample 23 (step 2) using1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.

[0567] mp: 169-170° C.

[0568]¹H-NMR (CDCl₃) δ: 8.81 (s, 1H), 8.14 (s, 1H), 7.98 (d, J=8 Hz,2H), 7.63-7.56 (m, 4H), 7.29 (d, J=8 Hz, 2H), 6.84 (s, 1H), 3.08 (s,3H).

[0569] Anal. Calcd. for C₂₀H₁₄N₃O₂F₃S₂ ¼H₂O: C, 52.91; H, 3.22; N, 9.26.Found: C, 53.02; H, 3.24; N, 9.30.

Example 25

[0570]4-[5-[4-(5-Chloro-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0571]4-[5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl-1-phenylsulfonamide(step 1)

[0572] To a stirred solution of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(2.09 g, 4.69 mmol) in dioxane (28 mL) was added bis(pinacolato)diboron(1.31 g, 5.16 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.14 g, 0.257mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.21 g,0.257 mmol) and potassium acetate (1.38 g, 14.1 mmol) at roomtemperature under nitrogen. The mixture was stirred at 80° C. for 20hours, and cooled down to room temperature. The reaction mixture wasdiluted with water and the whole was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate/hexane (1/3) to give the title compound (1.85 g, 80%yield).

[0573]¹H-NMR (CDCl₃) δ: 7.90 (d, J=8 Hz, 2H), 7.79 (d, J=7 Hz, 2H), 7.46(d, J=8 Hz, 2H), 7.22 (d, J=7 Hz, 2H), 6.80 (s, 1H), 4.95 (s, 2H), 1.35(s, 12H).

[0574]4-[5-[4-(5-Chloro-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0575] To a stirred solution of4-[5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.10 g, 0.203 mmol) in DME (3 mL) was added 2-bromo-5-chlorothiophen(0.048 g, 0.244 mmol), dichlorobis(triphenylphosphine)palladium (0.1 g,0.14 mmol) and saturated NaHCO₃ solution (1 mL) at room temperatureunder nitrogen. The mixture was heated at reflux temperature for 20hours, and cooled down to room temperature. The reaction mixture waspurified by flash chromatography eluting with ethyl acetate/hexane(1/4). The resulting solid was recrystallized with CH₂Cl₂-hexane to givethe title compound (0.045 g, 46% yield).

[0576] mp: 181-183° C.

[0577]¹H-NMR (CDCl₃) δ: 7.94 (d, J=9 Hz, 2H), 7.51 (d, J=9 Hz, 4H), 7.23(d, J=9 Hz, 2H), 7.13 (d, J=4 Hz, 1H), 6.92 (d, J=4 Hz, 1H), 6.80 (s,1H), 4.92 (s, 2H).

[0578] Anal. Calcd. for C₂₀H₁₃ClF₃N₃O₂S₂: C, 49.64; H, 2.71; N, 8.68.Found: C, 49.64; H, 3.10; N, 8.48.

Example 26

[0579]4-[5-[4-(1H-Imidazol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0580] 4,4,4-Trifluoro-1-[4-(1-Imidazolyl)phenyl]butane-1,3-dione (Step1)

[0581] To a THF (5 mL) solution of 1,1,1,3,3,3-hexamethyldisilazane(0.178 g, 1.1 mmol) was added n-butyl lithum (1.6 M solution in hexane,0.72 mL, 1.2 mmol) at 0° C. under nitrogen, and the mixture was stirredfor 30 minutes, and cooled to −78° C. 4-(1-Imidazolyl)acetophenone(prepared according the method of M. A. Khan et. al., J. Chem. Soc. C.,1970, 85., 0.186 g, 1.0 mmol) was added to the mixture, and residue wasstirred for 1 hour. Ethyl trifluoroacetate (0.17 g, 1.2 mmol) was addedto the reaction mixture, the residue was warm to room temperature. Thereaction mixture was poured into ice water and the whole was extractedwith ethyl acetate (30 mL×2). The organic layer was washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The resulting solid waswashed with small amount of ethyl acetate to give the title compound(0.163 g).

[0582]¹H-NMR (DMSO d₆) δ: 8.34 (s, 1H), 7.94 (d, J=9 Hz, 2H), 7.82 (d,J=2 Hz, 1H), 7.70 (d, J=9 Hz, 2H), 7.13 (s, 1H), 6.02 (s, 1H).

[0583]4-[5-[4-(1H-Imidazol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0584] A mixture of4,4,4-Trifluoro-]-[4-(1-Imidazolyl)phenyl]butane-1,3-dione (0.16 g, 0.57mmol), 4-sulphonamidophenylhydrazine hydrochloride (commerciallyavailable from Maybridge Chem. Co. 0.14 g, 0.62 mmol) and absoluteethanol (2-0 mL) was heated at reflux temperature for 20 hour. Aftercooling, ethanol was removed under reduced pressure, then, water (100mL) was added to the mixture. The whole was extracted with ethyl acetate(100 mL), the organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purifed by flash chromatographyon silica(NH-silica gel, FUJI SILISIA CHEMICAL LTD. DM2035) eluting withethyl acetate/CH₂Cl₂/methanol (1/1/0.1). The resulting solid wasrecrystallized with ethyl acetate-diisopropyl ether to give the titlecompound (0.085 g, 35% yield).

[0585] mp: 231-231.5° C.

[0586]¹H-NMR (DMSO d₆) δ: 8.36 (s, 1H), 7.90 (d, J=9 Hz, 2H), 7.83 (br,1H), 7.76 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz. 2H), 7.52 (br. 2H), 7.47 (d,J=9 Hz, 2H), 7.32 (s, 1H), 7.12 (s, 1H).

[0587] Anal. Calcd. for C₁₉H₁₄N₅O₂F₃S ¼H₂O: C, 52.11; H, 3.34; N, 15.99.Found: C, 52.04; H, 3.43; N, 15.96.

Example 27

[0588]4-[5-[4-(2,5-Dimethylpyrrol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0589]4,4,4-Trifluoro-1-[4-(2,5-Dimethylpyrrol-1-yl)phenyl]butane-1,3-dione(Step 1)

[0590] To a THF (20 mL) solution of 1,1,1,3,3,3-hexamethyldisilazane(1.3 g, 8.1 mmol) was added n-butyllithum (1.55 M solution in hexane,5.2 mL, 8.1 mmol) at 0° C. under nitrogen, and the mixture was stirredfor 30 minutes, and cooled to −78° C. 4-(2,5-Dimethylpyrrol-1-yl)acetophenone (commercially available fromLancaster Synthesis, 1.56 g, 7.3 mmol) was added to the mixture, andresidue was stirred for 1 hour. N-Trifluoroacetylimidazol (1.44 g, 8.8mmol) was added to the reaction mixture, the residure was stirred for 3hour. The reaction mixture was poured into water and the whole wasextracted with ethyl acetate (50 mL×2). The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica(ethyl acetate/Hexane=1/1) togive the title compound (0.75 g).

[0591]¹H-NMR (CDCl₃) δ 7.99 (d, J=9 Hz, 2H), 7.24 (d. J 9 Hz. 2H), 6.45(s, 1H), 5.19 (s, 2H). 2.04 (s, 3H), 2.0 (s, 3H).

[0592]4-[5-[4-(2,5-Dimethylpyrryol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide. (Step 2)

[0593] The subtitled compound was prepared according to the procedure ofExample 26 (step 2) using4,4,4-trifluoro-1-[4-(2,5-dimethylpyrrol-1-yl)phenyl]butane-1,3-dione,instead of 4,4,4-trifluoro-1-[4-(1-imidazolyl)phenyl]butane-1,3-dione.

[0594] mp: 210-211° C.

[0595]¹H-NMR (CDCl₃) δ: 7.95 (ddd, J=9, 2, 2 Hz, 2H), 7.53 (ddd, J=9, 2,2 Hz, 2H), 7.34 (ddd, J=9, 2, 2 Hz. 2H), 7.26-7.22 (2H), 6.85 (s, 1H),5.93 (s, 2H), 4.85 (br, 2H), 2.05 (s, 6H).

[0596] Anal. Calcd. for C₂₂H₁₉N₄O₂F₃S₁: C, 57.38; H, 4.16; N, 12.17.Found: C, 57.32; H, 4.35; N, 12.37.

Example 28

[0597]4-[5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide

[0598] 4,4,4-Trifluoro-1-4-(3-thienyl)phenyl]butane-1,3-dione (Step 1)

[0599] The subtitled compound was prepared according to the procedure ofExample 27 (step 1) using 4-(3-thienyl)acetophenone (prepared accordingthe method of Heterocycles, 1990, 31, 1951.) instead of4-(2,5-dimethylpyrrol-1-yl)acetophenone.

[0600]¹H-NMR (CDCl₃) δ: 7.95-7.90 (m, 2H), 7.8-7.7 (m, 2H), 7.68-7.6 (m,2H), 7.20-7.15 (m, 1H), 6.32 (1H).

[0601]4-[5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 2)

[0602] The title compound was prepared according to the procedure ofExample 26 (step 2) using4,4,4-Trifluoro-1-[4-(3-thienyl)phenyl]butane-1,3-dione, instead of4,4,4-trifluoro-1-[4-(1-imidazolyl)phenyl]butane-1,3-dione.

[0603] mp: 207.5-208° C.

[0604]¹H-NMR (CDCl₃) δ: 7.94 (ddd, J=9, 2, 2 Hz, 2H), 7.62 (ddd, J=9, 2,2 Hz, 2H), 7.52 (ddd, J=9, 2, 2 Hz, 2H), 7.37 (dd, J=5, 1 Hz, 1H), 7.34(dd, J=4, 1 Hz, 1H), 7.30-7.22 (m, 2H), 7.11 (dd, J=5, 4 Hz, 1H), 6.81(s, 1H), 4.87 (br 2H).

[0605] Anal. Calcd. for C₂₀H₁₄N₃O₂F₃S₂: C, 53.44; H, 3.14; N, 9.35.Found: C, 53.71; H, 3.15; N, 9.29.

Example 29

[0606]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0607] 4,4,4-Trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione (Step 1)

[0608] The title compound was prepared according to the procedure ofExample 27 (step 1) using 4-(2-furyl)acetophenone (prepared accordingthe method of Heterocycles, 1990, 31, 1951.) instead of4-(2,5-dimethylpyrrol-1-yl)acetophenone.

[0609]¹H-NMR (CDCl₃) δ: 8.04 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz. 2H), 7.68(s, 1H), 6.99 (d, J=3 Hz, 1H), 6.58 (dd, J=3, 2 Hz, 1H) 6.41 (s, 1H).

[0610] 4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-v1]-1-phenyl sulfonamide. (Step 2)

[0611] The title compound was prepared according to the procedure ofExample 26 (step 2) using4,4,4-Trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione, instead of4,4,4-trifluoro-1-[4-(1-imidazolyl)phenyl]butane-1,3-dione.

[0612] mp: 192-193° C.

[0613]¹H-NMR (CDCl₃) δ: 7.92 (ddd, J=9, 2, 2 Hz, 2H), 7.67 (ddd, J=9, 2,2 Hz, 2H), 7.53-7.48 (m, 3H), 7.24 (ddd, J=9, 2, 2 Hz, 2H), 6.80 (s,1H), 6.73 (dd, J=3, 1 Hz, 1H), 6.51 (dd, J=3, 2 Hz, 1H), 4.91 (s, 2H).

[0614] Anal. Calcd. for C₂₀H₁₄N₃O₃F₃S: C, 55.43; H, 3.26; N, 9.70.Found: C, 55.50; H, 3.38; N, 9.52.

Example 30

[0615]4-[5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0616] Trifluoromethanesulfonic acid 4-acetyl-2methylphenyl ester (Step1)

[0617] To a stirred soluition of 1-(4-hydroxy-3-methylphenyl)ethanone(3.76 g, 25.0 mmol) in CH₂Cl₂ (150 mL) was added 2,6-lutidine (3.21 g,30.0 mmol), 4-dimethylaminopyridine (0.61 g, 5.0 mmol),trifluoromethanesulfonic anhydride (8.46 g, 30.0 mmol) at −30° C. undernitrogen, and the mixture was stirred for 1 hour, and then allowed towarm up to room temperature for 2 hours. The reaction mixture wasdiluted with water and the whole was extracted with CH₂Cl₂. The organiclayer was washed with brine, dried over MgSO₄, and concentrated in vacuoto give 7.06 g of brown oil. The sub title compound was used for nextreaction without purification.

[0618] 1-[4-(2-Furyl)-3-methylphenyl]ethanone (Step 2)

[0619] To a stirred solution of trifluoromethanesulfonic acid4-acetyl-2methylphenyl ester (1.19 g, 4.2 mmol) in 1,4-dioxane (40 mL)was added 2-(tributylstannyl)furan (1.81 g, 5.05 mmol), lithium chloride(0.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium (0.49 g,0.42 mmol) under nitrogen. The mixture was heated at reflux temperaturefor 2 hours, and cooled down to room temperature. The reaction mixturewas diluted with water and the whole was extracted with diethylether.The organic layer was washed with saturated NaHCO₃ aqueous solution,brine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate/hexane(1/10) to give title compound (0.845 g, quant).

[0620]¹H-NMR (CDCl₃) δ: 7.83-7.82 (m, 3H), 7.56 (d, J=2 Hz, 1H), 6.70(d, J=4 Hz, 1H), 6.55 (dd, J=4, 2 Hz, 1H), 2.61 (s, 3H), 2.57 (s, 3H).

[0621] 4,4,4-Trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione(Step 3)

[0622] To a stirred soluition of ethyl trifluoroacetate (0.66 g, 4.67mmol) in t-butylmethylether (15 mL) was added sodium methoxide (28 wt. %solution in methanol; 1.2 mL, 4.98 mmol) over 2 min. A solution of1-[4-(2-furyl)-3-methylphenyl]ethanone in t-butylmethylether (4 mL) wasadded dropwise over 5 minutes, and the mixture was stirred for 20 hours.2N HCl (10 mL) was added, and the whole was extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo to give 1.12 g of brown oil. The compound was usedfor next reaction without purification.

[0623]4-[5-[4-(2-Furyl-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 4)

[0624] To a stirred soluition of4,4,4-trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione (0.53 g,1.80 mmol) in ethanol (22.5 ml) was added (4-sulfamoylphenyl)hydrazinehydrochloride (0.44 ml, 1.98 mmol), and the mixture was heated at refluxtemperature for 16 hours. The mixture was cooled down to roomtemperature, and concentrated in vacuo. The residue was dissolved inethyl acetate, washed with brine, dried over MgSO₄, and concentrated inin vacuo. The residue was purified by flash chromatography eluting withethyl acetate/hexane (1/3). The resulting solid was recrystallized withdichloromethane-hexane to give the title compound (0.16 g, 20% yield).

[0625]¹H-NMR (CDCl₃) δ: 7.86 (dd, J=9, 2 Hz, 2H), 7.66 (dd, J=8, 2 Hz,1H), 7.49-7.43 (m, 3H), 7.17 (s, 1H), 6.99 (d, J=8 Hz, 1H), 6.77 (s,1H), 6.60 (d, J=4 Hz, 1H), 6.50 (dd, J=4, 2 Hz, 1H), 5.43 (s, 2H), 2.45(s, 3H).

[0626] Anal. Calcd. for C₂₁H₁₆N₃O₃F₃S {fraction (1/10)}H₂O: C, 56.15; H,3.63; N, 9.35. Found: C, 56.29; H, 3.83; N, 8.96.

Example 31

[0627]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole

[0628] The title compound was prepared according to the procedure ofExample 30 (step 4) using (4-methylsulfonyl)hydrazine hydrochlorideinstead of (4-sulfamoylphenyl)hydrazine hydrochloride.

[0629] mp: 174-176° C.

[0630]¹H-NMR (CDCl₃) δ: 7.95 (d, J=9 Hz, 2H), 7.70 (d, J=8 Hz, 1H), 7.58(d, J=9 Hz, 2H), 7.53 (d, J=2 Hz, 1H), 7.19 (s, 1H), 7.04 (dd, J=8, 2Hz, 1H), 6.80 (s, 1H), 6.64 (d, J=4 Hz, 1H), 6.53 (dd, J=4, 2 Hz, 1H),3.06 (s, 3H), 2.49 (s, 3H).

[0631] Anal. Calcd. for C₂₂H₁₇N₂O₃F₃S: C, 59.19; H, 3.84; N, 6.27.Found: C, 58.90; H, 4.17; N, 6.44.

Example 32

[0632]3-[4-(3-Thienyl)phenyl]4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone

[0633] 4-(3-Thienyl)phenylacetic acid (Step 1)

[0634] A mixture of 4-bromophenylacetic acid (1.08 g, 5 mmol),3-thiopheneboronic acid (0.7 g, 5.5 mmol), NaHCO₃ (1.68 g, 20 mmol), anddichlorobis(triphenylphosphine)palladium (0.35 g, 0.5 mmol) in DME-water(21 mL-7 mL) was heated at reflux temperature for 2 hours undernitrogen. After cooling, the reaction mixture was partitioned betweenEt₂O (80 mL) and saturated aqueous NaHCO₃ (30 mL). The organic layer waswashed with saturated aqueous NaHCO₃ (30 mL) again. The combined aqueouslayer was acidified with 2N HCl solution and the whole extracted withCH₂Cl₂ (50 mL×3). The combined organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography (SiO₂) eluting with ethyl acetate/hexane (1/1) togive the subtitle compound (0.56 g, 51% yield).

[0635]¹H-NMR (CDCl₃) δ: 7.56 (d, J=8.2 Hz, 2H), 7.44 (dd, J=2.6, 1.8 Hz,1H), 7.38 (d, J=2.6 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.32 (d, J=8.2 Hz.2H), 3.68 (s, 2H).

[0636] 2-Bromo-1-[4-(methylsulfonyl)phenyl]ethanone

[0637] To a stirred solution of 4-(methylthio)acetophenone (5 g, 30mmol) in CH₂Cl₂ (60 mL) was added m-chloroperbenzoic acid (70% purity,10.35 g, 60 mmol) in a portionwise at 0° C. After stirring for 2 hours,the mixture was poured into saturated aqueous NaHCO₃ (100 mL). The wholewas extracted with CH₂Cl₂ (100 mL×3), the combined organic layer washedwith water, brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography (SiO₂) eluting with ethylacetate/hexane (1/1) to give 4-(methylsulfonyl)acetophenone (4.86 g, 82%yield).

[0638]¹H-NMR (CDCl₃) δ: 8.14 (d, J=8.6 Hz, 2H), 8.05 (d, J=8.6 Hz, 2H),3.09 (s, 3H), 2.68 (s, 3H).

[0639] To a solution of 4-(methylsulfonyl)acetophenone (4.85 g, 24.5mmol) in CHCl₃ (70 ml) was added aluminum chloride (1 mg) and bromine(1.1 mL) in CHCl₃ (8.5 mL) dropwise. The mixture was stirred overnight,and poured into water. The whole was extracted with ethyl acetate (50mL×2), the combined organic layer was dried over MgSO₄, and concentratedin vacuo. The resulting residue was recrystallized from ethylacetate/hexane (1/1) to give the subtitle compound (5.28 g, 78% yield).

[0640]¹H-NMR (CDCl₃) δ: 8.21-8.14 (m, 2H), 8.11-8.05 (m, 2H), 4.46 (s,2H), 3.12 (s, 3H).

[0641]3-[4-(3-Thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone(Step 2)

[0642] To a suspension of 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone(0.27 g, 1 mmol) and 4-(3-thienyl)phenylacetic acid (0.19 g, 0.9 mmol)in acetonitrile (5 mL) was added Et₃N (0.33 mL) at 0° C. under nitrogen.After stirring for 20 minutes at room temperature, the mixture waschilled in ice bath. DBU (0.29 mL) was added to the mixture, and stirredfor 20 minutes at 0° C. To the mixture was added 1N HCl solution (8 mL)and ice-water (10 mL), and the mixture was stirred for 2 minutes. Thewhole was extracted with CH₂Cl₂ (50 mL×3), the combined organic layerwashed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate/hexane (1/1) followed by recrystallization from ethylacetate/hexane to provide the title compound (0.15 g, 39% yield).

[0643] mp: 220-222° C.

[0644]¹H-NMR (CDCl₃) δ: 7.95 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H),7.55 (d, J=8.6 Hz, 2H), 7.51 (dd, J=2.6, 1.6 Hz, 1H), 7.44 (d, J=8.4 Hz,2H), 7.40 (d, J=2.6 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 5.20 (s, 2H), 3.08(s, 3H).

[0645] Anal. Calcd. for C₂₁H₁₆O₄S₂: C, 63.62; H, 4.07. Found: C, 63.48;H, 4.33.

[0646] mS (ESI): 395 (M−1)

Example 33

[0647]3-[4-(2-Thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone

[0648] 4-(2-Thienyl)phenylacetic acid

[0649] The subtitle compound was prepared according to the procedure ofExample 32 using 2-thiopheneboronic acid instead of 3-thiopheneboronicacid in step 1.

[0650]¹H-NMR (CDCl₃) δ: 7.56 (d, J=8.2 Hz, 2H), 7.29-7.25 (m, 4H), 7.06(dd, J=5.1, 3.6 Hz, 1H), 3.64 (s, 2H).

[0651]3-[4-(2-Thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone

[0652] The title compound was prepared according to the procedure ofExample 32 using 4-(2-thienyl)phenylacetic acid instead of4-(3-thienyl)phenylacetic acid in step 2.

[0653] mp: 198-201° C.

[0654]¹H-NMR (CDCl₃) δ: 7.95 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H),7.55 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.37 (dd, J=3.6, 1.2 Hz,1H), 7.33 (dd, J=5.1, 1.2 Hz, 1H), 7.10 (dd, J=5.1, 3.6 Hz, 1H), 5.20(s, 2H), 3.09 (s, 3H).

[0655] Anal. Calcd. for C₂₁H₁₆O₄S₂ 0.2H₂O: C, 63.04; H, 4.13. Found: C,63.01; H, 4.31.

[0656] mS (ESI): 395 (M−1)

Example 34

[0657]3-[4-(3-Furyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone

[0658] 4-(3-Furyl)phenylacetic acid

[0659] The subtitle compound was prepared according to the procedure ofExample 32 using 3-furanboronic acid instead of 3-thiopheneboronic acidin step 1.

[0660]¹H-NMR (CDCl₃) δ: 7.70 (br.s, 1H), 7.46 (t. J=1:6 Hz. 1H), 7.42(d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 6.94 (br.s, 1H), 3.63 (s,2H).

[0661] 3-[4-(3-Furyl)phenyl]-4-[4-(methylsulfonyl)phenyl-2-(5H)-furanone

[0662] The title compound was prepared according to the procedure ofExample 32 using 4-(3-furyl)phenylacetic acid instead of4-(3-thienyl)phenylacetic acid in step 2.

[0663] mp: 188-190° C.

[0664]¹H-NMR (CDCl₃) δ: 7.94 (d, J=8.7 Hz, 2H), 7.77 (dd, J=1.5, 1.0 Hz,1H), 7.58-7.48 (m, 5H), 7.42 (d, J=8.6 Hz, 2H), 6.71 (dd, J=2.0, 1.0 Hz,1H), 5.19 (s, 2H), 3.08 (s, 3H).

[0665] Anal. Calcd. for C₂₁H₁₆O₅S 0.4H₂O: C, 65.07; H, 4.37. Found: C,65.01; H, 4.58.

[0666] mS (ESI): 379 (M−1)

Example 35

[0667]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-1-[4-(2-furyl)phenyl]-2-methyl-1H-pyrrole

[0668] 3-Fluoro-4-(methylthio)benzaldehyde (Step 1)

[0669] A mixture of 3,4-difluorobenzaldehyde (4.26 g, 30 mmol) andsodium thiomethoxide (2.1 g, 30 mmol) in DMF (40 mL) was heated at 90°C. for 1 hour. After cooling, 2N aqueous HCl was added to the mixture.The whole was extracted with Et₂O (70 mL×3), the combined organic layerwashed with water, brine, dried over MgSO₄, and concentrated in vacuo.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/hexane (1/10) to provide the subtitle compound (3.1g, 61% yield) as a colorless oil.

[0670]¹H-NMR (CDCl₃) δ: 9.91 (d, J=2.0 Hz, 1H), 7.63 (dd, J=8.0, 1.6 Hz,1H), 7.50 (dd, J=10, 1.6 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 2.54 (s, 3H).

[0671] 1-[3-Fluoro-4-(methylsulfonyl)phenyl]pentane-1,4-dione (Step 2)

[0672] To a stirred solution of 3-fluoro-4-(methylthio)benzaldehyde(3.04 g, 17.9 mmol) in ethanol (12 mL) was added methyl vinyl ketone(1.3 mL, 15.5 mmol), 3-benzyl-5-(2-hydroxyethyl)₄-methylthiazoliumchloride (0.84 g, 3.1 mmol), and Et₃N (4.32 mL, 31 mmol) at roomtemperature. After stirring for 2 hours, volatiles were removed byevaporation. The residue was taken up with ethyl acetate (200 mL), andwashed with water (120 mL), dil. aqueous HCl (120 mL), water (120 mL),brine (120 mL), dried over MgSO₄, and concentrated in vacuo. Theresulting crude residue was purified by flash chromatography on silicagel eluting with ethyl acetate/hexane (1/2) to provide1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 73% yield).To a stirred suspension of1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 11.25 mmol)in methanol (50 mL) was added Oxone (14.14 g, 23 mmol) in water (50 mL)at room temperature. After stirring for 5 hours, the mixture was dilutedwith water. The whole was extracted with CH₂Cl₂ (50 mL×4), the combinedorganic layer washed with brine, dried over MgSO₄, and evaporated invacuo to give the subtitle compound (2.8 g, 66% yield).

[0673]¹H-NMR (CDCl₃) δ: 8.09 (dd, J=8.1, 6.6 Hz, 1H), 7.92 (dd, J=8.1,1.5 Hz, 1H), 7.81 (dd, J=10.4, 1.6 Hz, 1H), 3.25 (d, J=0.6 Hz, 3H),3.28-3.20 (m, 2H), 3.00-2.91 (m, 2H), 2.26 (s, 3H).

[0674]1-(4-Bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole(Step 3)

[0675] A mixture of1-[3-fluoro-4-(methylsulfonyl)phenyl]pentane-1,4-dione (2.8 g, 10.3mmol), 4-bromoaniline (2.12 g, 12.3 mmol), and p-toluenesulfonic acid(150 mg) in toluene (250 mL) was heated at reflux temperature usingDean-Stark apparatus. After cooling down, volatiles were removed byevaporation. The residue was purified by flash chromatography on silicagel eluting with ethyl acetate/hexane (1/5) to give the subtitlecompound (4 g, 95% yield).

[0676]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-1-[4-(2-furyl)phenyl-2-methyl-1H-pyrrole(Step 4)

[0677] To a stirred suspension of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole(0.41 g, 1 mmol), 2-furanboronic acid (0.14 g, 1.26 mmol), NaHCO₃ (0.19g, 2.3 mmol) in DME-water (6 mL-2 mL) was addeddichlorobis(triphenylphosphine)palladium (80 mg, 0.115 mmol) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 6 hours. After cooling, volatiles were removed by evaporation. Theresidue was purified by flash chromatography on silica gel eluting withethyl acetate/hexane (1/2) to give the title compound (0.24 g, 61/oyield).

[0678] mp: 179-182° C.

[0679]¹H-NMR (CDCl₃) δ: 7.73 (d, J=8.3 Hz. 2H), 7.65 (t, J=8.1 Hz, 1H).7.51 (br. s, 1H), 7.17 (d, J=8.3 Hz. 2H). 6.95 (d, J=8.4 Hz, 1H), 6.89(d, J=12 Hz. 1H). 6.73 (d, J=3.3 Hz, 1H), 6.55 (d, J=3.3 Hz, 1H), 6.52(br.s, 1H), 6.14 (d, J=3.6 Hz. 1H), 3.15 (s, 3H), 2.15 (s, 3H).

[0680] Anal. Calcd. for C₂₂H₁₈FNO₃S: C, 66.82; H, 4.59; N, 3.54. Found:C, 66.73; H, 4.82; N, 3.32.

Example 36

[0681]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-1-[4-(3-furyl)phenyl]-2-methyl-1H-pyrrole

[0682] The title compound was prepared according to the procedure ofExample 35 using 3-furanboronic acid instead of 2-furanboronic acid instep 4.

[0683] mp: 147-150° C.

[0684]¹H-NMR (CDCl₃) δ: 7.79 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.55 (d,J=8.2 Hz, 2H), 7.52 (t, J=1.5 Hz, 1H), 7.17 (d, J=8.2 Hz, 2H), 6.95 (dd,J=8.4, 1.5 Hz, 1H), 6;88 (dd, J=11.9, 1.5 Hz, 1H), 6.73 (br. s, 1H),6.55 (d, J=3.6 Hz, 1H), 6.14 (d, J=3.6 Hz, 1H), 3.16 (s, 3H), 2.16 (s,3H).

[0685] Anal. Calcd. for C₂₂H₁₈FNO₃S: C, 66.82; H, 4.59; N, 3.54. Found:C, 66.83; H. 4.80; N, 3.26.

Example 37

[0686]23-Dimethyl-1-[4-(3-furyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0687] 1-[4-(methylsulfonyl)phenyl]-3-methylpentane-1,4-dione

[0688] To a stirred solution of 4-(methylsulfonyl)benzaldehyde (1.84 g,10 mmol) in ethanol (8 mL) was added 3-methyl-3-buten-2-one (0.8 g, 9.5mmol), 3-benzyl-5-(2-hydroxyethyl)₄-methylthiazolium chloride (0.51 g,1.9 mmol), and Et₃N (2.65 mL, 19 mmol) at room temperature. Afterstirring for 3 hours, volatiles were removed by evaporation. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate/hexane (1/2) to provide the subtitle compound (0.11 g).

[0689]¹H-NMR (CDCl₃) δ: 8.13 (d, J=8.2 Hz, 2H), 8.03 (d, J=8.2 Hz, 2H),3.57 (dd, J=18.0, 9.1 Hz, 1H), 3.34-3.21 (m, 1H), 3.08 (s, 3H), 2.90(dd, J=18.0, 4.1 Hz, 1H), 2.31 (s, 3H), 1.25 (d, J=7.4 Hz, 3H).

[0690]1-(4-Bromophenyl)-2,3-dimethyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0691] A mixture of1-[4-(methylsulfonyl)phenyl]-3-methylpentane-1,4-dione (110 mg, 0.41mmol), 4-bromoaniline (71 mg, 0.41 mmol), and p-toluenesulfonic acid (10mg) in toluene (3 mL) was heated at reflux temperature using Dean-Starkapparatus. After cooling down, volatiles were removed by evaporation.The residue was purified by flash chromatography on silica gel elutingwith ethyl acetate/hexane (1/3) to give the subtitle compound (110 mg,67% yield).

[0692]¹H-NMR (CDCl₃) δ: 7.68 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H),7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.40 (s, 1H), 3.02 (s,3H), 2.30 (s, 3H), 2.04 (s, 3H).

[0693]2,3-Dimethyl-]-[4-(3-furyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0694] The title compound was prepared according to the procedure ofExample 35 using1-(4-bromophenyl)-2,3-dimethyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrroleinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrroleand 3-furanboronic acid instead of 2-furanboronic acid in step 4.

[0695] mp: 215-219° C.

[0696]¹H-NMR (CDCl₃) δ: 7.78 (t, J=1.5 Hz, 1H), 7.65 (d, J=8.6 Hz, 2H),7.55-7.49 (m, 3H), 7.19 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H), 6.72(dd, J=1.5, 0.8 Hz, 1H), 6.42 (s, 1H), 3.00 (s, 3H), 2.13 (s, 3H), 2.08(s, 3H).

[0697] Anal. Calcd. for C₂₃H₂₁NO₃S 0.5H₂O: C, 68.98; H, 5.54; N, 3.50.Found: C, 69.89; H, 5.48; N, 3.15.

Example 38

[0698]5-[4-(Methylsulfonyl)phenyl]-1-4-(3-furyl)phenyl]-2-methyl-1H-pyrrole

[0699]1-(4-Bromophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Step1)

[0700] A mixture of 1-[4-(methylsulfonyl)phenyl]pentane-1,4-dione (3 g,11.8 mmol), 4-bromoaniline (2.03 g, 11.8 mmol), and p-toluenesulfonicacid (150 mg) in toluene (250 mL) was heated at reflux temperature usingDean-Stark apparatus. After cooling down, volatiles were removed byevaporation. The residue was purified, by flash chromatography on silicagel eluting with ethyl acetate/hexane (1/3) to give the subtitlecompound (2.5 g, 54% yield).

[0701]¹H-NMR (CDCl₃) δ: 7.70 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H),7.17 (8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.50 (d, J=3.5 Hz, 1H), 6.14(d, J=3.5 Hz, 1H), 3.02 (s, 3H), 2.14 (s, 3H).

[0702]5-[4-(Methylsulfonyl)phenyl]-1-[4-(3-furyl)phenyl]-2-methyl-1H-pyrrole(Step 2)

[0703] The title compound was prepared according to the procedure ofExample 35 using1-(4-bromophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrroleinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrroleand 3-furanboronic acid instead of 2-furanboronic acid in step 4.

[0704] mp: 200-202° C.

[0705]¹H-NMR (CDCl₃) δ: 7.78 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.52 (m,3H), 7.22 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.72 (br.s, 1H),6.52 (d, J=3.6 Hz, 1H), 6.14 (d, J=3.6 Hz, 1H), 2.99 (s, 3H), 2.17 (s,3H).

[0706] Anal. Calcd. for C₂₂H₁₉NO₃S 0.2H₂O: C, 69.34; H, 5.13; N, 3.68.Found: C, 69.45; H, 5.19; N, 3.44.

Example 39

[0707]1-[4-(3-Furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0708]1-(4-Bromo-3-methylphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl)-1H-pyrrole

[0709] The subtitle compound was prepared according to the procedure ofExample 38 using 4-bromo-3-methylaniline instead of 4-bromoaniline instep 1.

[0710]¹H-NMR (CDCl₃) δ: 7.70 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H),7.20 (d, J=8.4 Hz, 2H), 7.04 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.4, 2.5 Hz,1H), 6.50 (d, J=3.6 Hz, 1H), 6.12 (d, J=3.6 Hz, 1H), 3.02 (s, 3H), 2.39(s, 3H), 2.13 (s, 3H).

[0711]1-[4-(3-Furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0712] The title compound was prepared according to the procedure ofExample 35 using1-(4-bromo-3-methylphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrroleinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrroleand 3-furanboronic acid instead of 2-furanboronic acid in step 4.

[0713] mp: 69-75° C.

[0714]¹H-NMR (CDCl₃) δ: 7.68 (d, J=8.4 Hz, 2H), 7.59 (br.s, 1H), 7.52(t, J=1.6 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H),7.06-6.97 (m, 2H), 6.63 (br.s, 1H), 6.52 (d, J=3.6 Hz, 1H), 6.13 (d,J=3.6 Hz, 1H), 3.00 (s, 3H), 2.38 (s, 3H), 2.16 (s, 3H).

[0715] Anal. Calcd. for C₂₃H₂₁NO₃S 0.2H₂O: C, 69.92; H, 5.46; N, 3.55.Found: C, 69.92; H, 5.52; N, 3.30.

Example 40

[0716] 1-[4-(2-Furyl)-3-methylphenyl]-2-meth,1-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0717]1-[4-(2-Furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0718] The title compound was prepared according to the procedure ofExample 35 using1-(4-bromo-3-methylphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrroleinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrolein step 4.

[0719] mp: 160-162° C.

[0720]¹H-NMR (CDCl₃) δ: 7.75 (d, J=8.9 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H),7.54 (d, J=1.8 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.07-7.02 (m. 2H), 6.62(d, J=3.3 Hz, 1H), 6.60-6.50 (m, 2H), 6.13 (d, J=3.6 Hz, 1H), 3.00 (s,3H), 2.49 (s, 3H), 2.16 (s, 3H).

[0721] Anal. Calcd. for C₂₃H₂₁NO₃S 0.35H₂O: C, 69.45; H, 5.50; N, 3.52.Found: C, 69.43; H, 5.44; N, 3.43.

Example 41

[0722]1-[3-Chloro-4-(3-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0723]1-(4-Bromo-3-chlorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0724] The subtitle compound was prepared according to the procedure ofExample 38 using 4-bromo-3-chloroaniline instead of 4-bromoaniline instep 1.

[0725]¹H-NMR (CDCl₃) δ: 7.73 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H),7.30 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.91 (dd, J=8.4, 2.5 Hz,1H), 6.49 (d. J=3.6 Hz, 1H), 6.13 (d, J=3.6 Hz, 1H), 3.03 (s, 3H), 2.15(s, 3H).

[0726]1-[3-Chloro-4-(3-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0727] The title compound was prepared according to the procedure ofExample 35 using1-(4-bromo-3-chlorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrroleinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1-pyrroleand 3-furanboronic acid instead of 2-furanboronic acid in step 4.

[0728] mp: 165-168° C.

[0729]¹H-NMR (CDCl₃) δ: 7.93 (br.s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.53(t, J=1.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.23(d, J=°0.2 Hz, 2H), 7.05 (dd, J=8.2, 2.2 Hz, 1H), 6.77 (br.s, 1H), 6.51(d, J=3.8 Hz, 1H), 6.15 (d, J=3.8 Hz, 1H), 3.02 (s, 3H), 2.19 (s, 3H).

[0730] Anal. Calcd. for C₂₂H₁₈ClNO₃S: C, 64.15; H, 4.40; N. 3.40. Found:C, 63.79; H. 4.54; N, 3.13.

Example 42

[0731] 1-[3-Chloro-4-(2-furyl)phenyl]-2-meth1-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0732] The title compound was prepared according to the procedure ofExample 35 using 1-(4-bromo-3-chlorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrolein step 4.

[0733] mp: 127-131° C.

[0734]¹H-NMR (CDCl₃) δ: 7.92 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H),7.55 (d, J=1.8 Hz, 1H), 7.30-7.20 (m, 4H), 7.10 (dd, J=8.9, 2.1 Hz, 1H),6.59-6.54 (m, 1H), 6.50 (d, J=3.5 Hz, 1H), 6.14 (d, J=3.6 Hz, 1H) 3.01(s, 3H), 2.18 (s, 3H).

[0735] Anal. Calcd. for C₂₂H₁₈ClNO₃S: C, 64.15; H, 4.40; N, 3.40. Found:C, 63.86; H, 4.56; N, 3.23.

Example 43

[0736] 1-(4-Biphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0737] The title compound was prepared according to the procedure ofExample 36 using 4-aminobiphenyl instead of 4-bromoaniline in step 1.

[0738] mp: 150-152° C.

[0739]¹H-NMR (CDCl₃) δ: 7.70-7.62 (m, 6H), 7.50-7.35 (m, 3H), 7.26-7.21(m, 4H), 6.53 (d, J=3.6 Hz, 1H), 6.15 (d, J=3.6 Hz, 1H), 3.00 (s, 3H),2.19 (s, 3H).

[0740] Anal. Calcd. for C₂₄H₂₁NO₂S: 0.4H₂° C., 73.03; H, 5.57; N, 3.55.Found: C, 73.20; H, 5.50; N, 3.49.

Example 44

[0741]1-[4-(2-Furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0742] 4-(2-Furyl)aniline. (Step 1)

[0743] To a suspension of 2-(4-nitrophenyl)furan (0.378 g, 2 mmol,prepared according to the method of Heterocycles, 1990, 31, 1951) inethanol (20 mL) was heated to 70° C. and added stannous chloridedihydrate (2.26 g, 10 mmol) and the mixture was stirred for 2 hours. Thereaction mixture was cooled to room temperature and poured into water(50 mL), the whole was extracted with ethyl acetate (30 mL×2). Theorganic layer was dried over Na₂SO₄, filtered through celite andconcentrated to give the crude subtitle compound (0.35 g).

[0744] mS (EI): m/z 159 (M⁺)

[0745]1-[4-(2-Furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole.(Step 2)

[0746] A mixture of 1-[4-(methylsulfonyl)phenyl]pentene-1,4-dione (0.305g, 1.2 mmol prepared according to the method of J. Med. Chem., 1997, 40,1619), 4-(2-furyl)aniline (0.35 g, 2 mmol), and p-toluenesulfonic acidmonohydrate (0.015 g) in toluene (40 mL) was heated at refluxtemperature for 16 hours using Dean-Stark apparatus. After cooling,volatiles were removed by evaporation. The residue was purified by flashchromatography eluting with hexane/ethyl acetate (4/1). The resultingsolid was recrystallized from CH₂Cl₂/hexane to give the title compound(0.11 g, 24.3% yield).

[0747] mp: 145-147° C.

[0748]¹H-NMR (CDCl₃) δ: 7.73-7.66 (m, 4H), 7.50 (d, J=1 Hz. 1H),7.24-7.15 (m, 4H), 6.71 (d, J=3 Hz, 1H), 6.53-6.50 (m, 2H), 6.14 (dd,J=1, 3 Hz, 1H), 3.00 (s, 3H), 2.17 (s, 3H).

[0749] Anal. Calcd. for C₂₂H₁₉NO₃S: C, 70.00; H, 5.07; N, 3.71. Found:C, 69.88; H, 5.18; N, 3.32.

[0750] mS (EI): m/z 377 (M⁺)

Example 45

[0751]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thienyl]phenyl]-1H-pyrrole

[0752] 4-(2-Thienyl)aniline. (Step 1)

[0753] The subtitle compound was prepared according to the procedure ofExample 44 (step 1) using 2-(4-nitrophenyl)thiophene (prepared accordingto the method of Heterocycles, 1990, 31, 1951).

[0754] mS (EI): m/z 175 (M⁺)

[0755]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thienyl)phenyl]-1H-pyrrole.(Step 2)

[0756] The title compound was prepared according to the procedure ofExample 44 (step 2) using 4-(2-thienyl)aniline.

[0757] mp: 185-186° C.

[0758]¹H-NMR (CDCl₃) δ: 7.71-7.63 (m, 4H). 7.38-7.32 (m, 2H), 7.25-7.10(m. 5H), 6.52 (d, J=4 Hz, 1H), 6.15 (dd, J=4, 1 Hz, 1H), 3.00 (s, 3H),2.18 (s, 3H).

[0759] Anal. Calcd. for C₂₂H₁₉NO₂S₂,0.1H₂O: C, 66.84; H, 4.90; N, 3.54.Found: C, 66.56; H, 4.97; N, 3.65.

[0760] mS (EI): m/z 393 (M⁺)

Example 46

[0761]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(3-thienyl)phenyl]-1H-pyrrole

[0762]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(3-thienyl)phenyl]-1H-pyrrole.

[0763] To a stirred solution of 2-methyl5-[4-(methylsulfonyl)phenyl]-1-(4-bromophenyl)-1H-pyrrole (0.2 g, 0.51mmol) in DME (6 mL) was added thiophene-3-boronic acid (0.079 g, 0.61mmol), bis(triphenylphosphine)palladium(II)chloride (0.04 g, 0.06 mmol)and saturated NaHCO₃ solution (2 mL) at room temperature under nitrogen.The mixture was heated at reflux temperature for 6 hours, and cooleddown to room temperature. The reaction mixture was filtered throughcelite, the filtrate was poured into water and the whole was extractedwith ethyl acetate (10 mL×3). The organic layer was washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby flash chromatography eluting with hexane/ethyl acetate (4/1). Theresulting solid was recrystallized from ethyl acetate/hexane to give thetitle compound (0.15 g, 75.0% yield).

[0764] mp: 187-188° C.

[0765]¹H-NMR (CDCl₃) δ: 7.69-7.63 (m, 4H), 7.53-7.51 (m, 1H), 7.43 (d,J=1 Hz, 1H), 7.42 (s, 1H), 7.23 (d, J=9 Hz, 2H), 7.18 (d, J=8 Hz, 2H),6.53 (d, J=3 Hz, 1H), 6.15 (dd, J=4, 1 Hz, 1H), 3.00 (s, 3H), 2.18 (s,33H).

[0766] Anal. Calcd. for C₂₂H₁₉NO₂S₂,0.2H₂O: C, 66.54; H, 4.92; N, 3.53.Found: C, 66.61; H, 5.01; N, 3.23.

[0767] mS (EI): m/z 393 (M⁺)

Example 47

[0768]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-pyrrolyl)phenyl]-1H-pyrrole

[0769] The title compound was prepared according to the procedure ofExample 46 using (1-tert-butoxycarbonyl)pyrrole-2-boronic acid, insteadof thiophene-3-boronic acid.

[0770] mp: 225-227° C.

[0771]¹H-NMR (CDCl₃) δ: 8.36 (brs, 1H), 7.66 (d J=9 Hz. 2H), 7.57 (d,J=9 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.16-7.14 (m. 1H), 7.12 (d, J=8 Hz.2H), 6.87 (dd, J=5, 3 Hz, 1H), 6.58-6.56 (m, 1H), 6.52 (d, J=3 Hz, 1H),6.13 (d, J=4 Hz, 1H), 2.99 (s, 3H), 2.17 (s, 3H).

[0772] Anal. Calcd. for C₂₂H₂₀N₂O₂S, 1.2H₂O: C, 66.38; H, 5.67; N, 7.04.Found: C, 66.60; H, 5.33; N, 6.73.

[0773] mS (EI): m/z 376 (M⁺)

Example 48

[0774]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[[4-(1-tert-Butoxycarbonyl)-2-pyrrolyl]phenyl]-1H-pyrrole

[0775] The title compound was prepared according to the procedure ofExample 46 using (1-tert-butoxycarbonyl)pyrrole-2-boronic acid, insteadof thiophene-3-boronic acid.

[0776] mp: 169-170° C.

[0777]¹H-NMR (CDCl₃) δ: 7.68 (d, J=9 Hz, 2H), 7.41-7.37 (m, 3H), 7.24(d, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 6.52 (d, J=4 Hz, 1H), 6.27-6.24(m, 2H), 6.15 (d, J=3 Hz, 1H), 3.00 (s, 3H), 2.18 (s, 3H), 1.56 (s, 9H).

[0778] Anal. Calcd. for C₂₇H₂₈N₂O₄S: C, 68.04; H, 5.92; N, 5.88. Found:C, 68.01; H, 6.10; N, 5.82.

[0779] mS (EI): m/z 476 (M⁺)

Example 49

[0780]2-Methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thiazolyl)phenyl]-1H-pyrrole

[0781]2-Methyl-5-[4-(methylsulfonyl)phenyl)-1-[4-(2-thiazolyl)phenyl]-1H-pyrrole.

[0782] To a stirred solution of thiazole (0.072 g, 0.85 mmol) inanhydrous ether (2 mL) was added n-BuLi (0.58 mL, 1.61 M solution inhexane, 0.94 mmol) at −78° C. under nitrogen, the mixture was stirredfor 30 minutes at −78° C., and then zinc chloride (2.55 mL, 1.0 Msolution in ether, 2.55 mmol) was added at −78° C., the mixture wasstirred for 30 minutes at −78° C. The reaction mixture was warmed to 0°C., and added the solution of 2-methyl5-[4-(methylsulfonyl)phenyl]-1-(4-bromophenyl)-1H-pyrrole (0.3 g, 0.77mmol) in THF (5 mL), tetrakis(triphenylphosphine)palladium (0) (0.088 g,0.08 mmol). The reaction mixture was heated at reflux temperature for 19hours, and cooled down to room temperature. The reaction mixture wasfiltered through celite, the filtrate was poured into water and thewhole was extracted with ethyl acetate (20 mL×3). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with hexane/ethylacetate (2/1). The resulting solid was recrystallized from CH₂Cl₂/hexaneto give the title compound (0.040 g, 13.2% yield).

[0783] mp: 190-191° C.

[0784]¹H-NMR (CDCl₃) δ: 8.03 (d, J=9 Hz, 2H), 7.90 (d, J=3 Hz, 1H), 7.69(d, J=9 Hz, 2H), 7.39 (d, 3 Hz, 1H), 7.25-7.21 (m, 4H), 6.53 (d, J=4 Hz,1H), 6.16 (dd, J=4, 1 Hz, 1H), 3.00 (s, 3H), 2.19 (s, 3H).

[0785] Anal. Calcd. for C₂₁H₁₈N₂O₂S₂ 0.6H₂O: C, 62.23; H, 4.77; N, 6.91.Found: C, 62.01; H, 4.70; N, 6.78.

[0786] mS (EI): m/z 395 (M⁺+1)

Example 50

[0787]2-Methyl-5-[4-(methylsulfonyl)phenyl]-4-[4-(2-thienyl)phenyl]oxazole

[0788]2-Methyl-5-[4-(methylsulfonyl)phenyl]4-[4-(2-thienyl)phenyl]oxazole.

[0789] To a stirred solution of2-methyl-5-[4-(methylsulfonyl)phenyl]-4-(4-bromophenyl)-oxazole (0.314g, 0.8 mmol) in DME (10 mL) was added thiophene-2-boronic acid (0.123 g,0.96 mmol), bis(triphenylphosphine)palladium(II)chloride (0.064 g, 0.09mmol) and saturated NaHCO₃ solution (3.2 mL) at room temperature undernitrogen. The mixture was heated at reflux temperature for 4.5 hours,and cooled down to room temperature. The reaction mixture was filteredthrough celite, the filtrate was poured into water and the whole wasextracted with ethyl acetate (10 mL×3). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by flash chromatography eluting with hexane/ethyl acetate(3/2). The resulting solid was recrystallized from ethyl acetate/hexaneto give the title compound (0.225 g, 71.2% yield).

[0790] mp: 183-185° C.

[0791]¹H-NMR (CDCl₃) δ: 7.92 (d, J=9 Hz, 2H). 7.81 (d, J=9 Hz, 2H),7.68-7.61 (m, 4H), 7.38 (dd, J=4, 1 Hz, 1H), 7.32 (dd, J=5, 1 Hz, 1H)7.11 (dd, J=4, 5 Hz, 1H) 3.09 (s, 3H), 2.60 (s, 3H).

[0792] Anal. Calcd. for C₂₁H₁₇NO₃S₂, 0.2H₂O: C, 63.20; H, 4.39; N, 3.51.Found: C, 63.22; H, 4.36; N, 3.21.

[0793] mS (EI): m/z 395 (M⁺)

Example 51

[0794]4-[4-(2-Furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole

[0795] The title compound was prepared according to the procedure ofExample 50 using furan-2-boronic acid, instead of thiophene-2-boronicacid.

[0796] mp: 143-144° C.

[0797]¹H-NMR (CDCl₃) δ: 7.91 (d, J=9 Hz, 2H), 7.80 (d, J=9 Hz, 2H), 7.72(d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, 2H), 7.50 (dd, J=2, 0.7 Hz, 1H), 6.72(dd, J=3, 0.7 Hz, 1H), 6.50 (dd, J=3, 2 Hz, 1H), 3.08 (s, 3H), 2.59 (s,3H).

[0798] Anal. Calcd. for C₂₁H₁₇NO₄S 0.2H₂O: C, 65.85; H, 4.58; N, 3.66.Found: C, 65.76; H, 4.611; N, 3.53.

[0799] mS (EI): m/z 379 (M⁺)

Example 52

[0800]1-[4-(Methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]4-(trifluoromethyl)-1H-imidazole

[0801] N-[4-(Methylsulfonyl)phenyl]4-(2-thienyl)benzenecarboximidamide.(Step 1)

[0802] To a suspension of 4-(methylsulfonyl)aniline (0.428 g, 2.5 mmol)in toluene (15 mL) at 0° C. was added over 5 minutes trimethylaluminum(3.83 mL, 0.98 M solution in hexane, 3.75 mmol). The reaction mixturewas warmed to room temperature and stirred for 3.5 hours. A solution of2-(4-cyanophenyl)thiophene (0.926 g, 5 mmol, prepared according to themethod of Heterocycles, 1990, 31, 1951) in toluene (10 mL) was addedover 5 minutes and the reaction mixture heated to 70° C. After 18.5hours, the reaction mixture was cooled to room temperature and pouredover a slurry of silicagel in chloroform-methanol (2:1, 150 mL). Afterfiltration, the residue was washed with a mixture of CH₂Cl₂-methanol(2:1, 75 mL). The combined filtrates were concentrated in vacuo, and theresulting yellowish solid was washed with hexane-ether (2:1, 100 mL) togive the subtitle compound (0.711 g).

[0803] mS (EI): m/z 356 (M⁺)

[0804]4-Hydroxy-1-[4-(methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole.(Step 2)

[0805] To a mixture ofN-[4-(methylsulfonyl)phenyl]-4-(2-thienyl)benzenecarboximidamide (0.7 g.1.96 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 2-propanol (30mL) was added 3-bromo-1,1,1-trifluoroacetone (0.449 g, 2.35 mmol). Afterthe reaction mixture was heated to 80° C. for 21 hours, the solvent wasremoved. The residue was redissolved in CH₂Cl₂ (50 mL) and washed withwater (30 mL×2). The organic fractions were combined, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude mixture was purified byflash chromatography eluting with hexane/ethyl acetate (2/1) to give thesubtitle compound (0.351 g, 30.1% yield, via 2 steps).

[0806]¹H-NMR (DMSO d₆) d: 7.80-7.74 (m, 4H), 7.64 (d, J=4 Hz, 2H), 7.53(d, J=9 Hz, 2H), 7.43 (s, 1H), 7.19-7.16 (m, 1H), 7.11 (d, J=9 Hz, 2H),4.51 (d, J=12 Hz, 1H), 3.97 (d, J=12 Hz, 1H), 3.17 (s, 3H).

[0807] mS (EI): m/z 466 (M⁺)

[0808]1-[4-(Methylsulfonyl)phenyl]-2-[4-(2-thieyl)phenyl]-4-(trifluoromethyl)-1H-imidazole.(Step 3)

[0809] A mixture of4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole(0.345 g, 0.74 mmol) and p-toluenesulfonic acid monohydrate (0.035 g) intoluene (40 mL) was heated to reflux for 7 hours. The reaction mixturewas cooled and the solvent removed under reduced pressure. The cruderesidue was redissolved in CH₂Cl₂ (50 mL) and the whole washed withwater, aqueous NaHCO₃ (30 mL), and brine. After dried over Na₂SO₄, andconcentration in vacuo. The crude mixture was purified by flashchromatography eluting with hexane/ethyl acetate (2/1). The resultingsolid was recrystallized from ethyl acetate-hexane to give the titlecompound (0.212 g, 63.9% yield).

[0810] mp: 95-97° C.

[0811]¹H-NMR (CDCl₃) δ: 8.05 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 2H),7.54-7.53 (m, 1H), 0.48 (d, J=9 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.36-7.31(m, 2H), 7.09 (dd, J=5, 4 Hz, 1H), 3.13 (s, 3H).

[0812] Anal. Calcd. for. C₂₁H₁₅F₃N₂O₂S₂: C, 56.24; H. 3.37: N. 6.25.Found: C, 56.15; H, 3.73; N, 6.00.

[0813] mS (EI): m/z 448 (M⁺)

Example 53

[0814]2-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole

[0815] N-[4-(Methylsulfonyl)phenyl]-4-(2-furyl)benzenecarboximidamide.(Step 1)

[0816] The subtitle compound was prepared according to the procedure ofExample 52 (step 1) using 2-(4-cyanophenyl)furan prepared according tothe method of Heterocycles, 1990, 31, 1951).

[0817] mS (EI): m/z 339 (M⁺−1)

[0818]4-Hydroxy-1-[4-(methylsulfonyl)phenyl]-2-[4-(2-furyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole.(Step 2)

[0819] The subtitle compound was prepared according to the procedure ofExample 52 (step 2) usingN-[4-(Methylsulfonyl)phenyl]-4-(2-furyl)benzenecarboximidamide.

[0820] mS (EI): m/z 450 (M⁺)

[0821]2-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole.(Step 3)

[0822] The title compound was prepared according to the procedure ofExample 52 (step 3) using4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-[4-(2-furyl)phenyl]-4-(trifluoromethyl)4,5-dihydro-1H-imidazole.

[0823] mp: 82-84° C.

[0824]¹H-NMR (CDCl₃) δ: 8.04 (d, J=9 Hz, 2H), 7.61 (d, J=8 Hz, 2H),7.53-7.45 (m, 4H), 7.38 (d, J=8 Hz, 2H), 6.71 (d, J=3 Hz, 1H), 6.49 (m,1H), 3.12 (s, 3H).

[0825] Anal. Calcd. for. C₂₁H₁₅F₃N₂O₃S, 0.5H₂O: C, 57.14; H, 3.65; N,6.35. Found: C, 57.23; H, 3.89; N, 6.13.

[0826] mS (EI): m/z 432 (M⁺)

Example 54

[0827] 2-[4-(2-Furyl)phenyl-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole

[0828] 4-Sulfamoyl-N-[4-(2-furyl)benzylidene]aniline. (Step 1)

[0829] A mixture of 2-(4-formylphenyl)furan (0.335 g, 1.95 mmol,prepared according to the method of Heterocycles, 1990, 31, 1951),sulfanilamide (0.336 g, 1.95 mmol) in ethanol (8 mL) was heated atreflux temperature for 2.5 hour. After cooling to room temperature, thecrystals which collected by filtration and washed with ethanol to givethe subtitle compound (0.378 g).

[0830]¹H-NMR (DMSO-d₆) δ: 8.65 (s, 1H), 8.01 (d, J=8 Hz, 2H), 7.89-7.84(m, 5H), 7.42-7.34 (m, 4H), 7.15 (d, J=3 Hz, 1H), 6.67 (dd, J=3, 2 Hz,1H).

[0831] α-4-Sulfamoylanilino-α-[4-(2-furyl)phenyl]acetnitrile. (Step 2)

[0832] To a suspension of 4-sulfamoyl-N-[4-(2-furyl)benzylidene]aniline(0.37 g, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. was addedtrimethylsilyl cyanide (0.135 g, 1.36 mmol), zinc chloride (1.36 mL, 1.0M solution in ether, 1.36 mmol). The temperature of the reaction mixturewas then allowed to return to room temperature, and the mixture wasstirred overnight. The reaction mixture was poured into water and thewhole was extracted with ethyl acetate (20 mL×2). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated to give thesubtitle compound (0.288 g). ¹H-NMR (DMSO-d₆) δ: 7.84-7.78 (m, 3H),7.65-7.60 (m, 4H), 7.39 (d, J=9 Hz, 1H), 7.04-7.01 (m, 3H), 6.91 (d, J=9Hz, 2H), 6.62 (dd, J=3, 2 Hz, 1H), 6.16 (d, J=9 Hz, 1H).

[0833] mS (EI) m/z 353 (M⁺)

[0834] 2-[4-(2-Furyl)phenyl]4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole.(Step 3)

[0835] To a suspension of aα-4-sulfamoylanilino-α-[4-(2-furyl)phenyl]acetnitrile (0.28 g, 0.79mmol) in anhydrous THF (3 mL) at −70° C. was added methacrolein (0.061g, 0.87 mmol), and then dropwise lithium bis(trimethylsilyl)amide (0.83mL, 1.0 M solution in hexane, 0.83 mmol). The reaction mixture wasstirred at −60° C. to −65° C. for 1 hour, and then the temperature ofthe reaction mixture was allowed to return to room temperature, and themixture was stirred for a further 2 hours. The reaction mixture wasadded a saturated aqueous solution of NH₄Cl (10 mL) and the whole wasextracted with ethyl acetate (10 mL×2). The organic layer was washedwith water, dried over Na₂SO₄, and concentrated in vacuo. The residuewas redissolved in toluene (5 mL) and heated at reflux temperature for 1hour. The reaction mixture was concentrated in vacuo. The residue waspurified by thin-layer chromatography eluting with hexane/ethyl acetate(2/1). The resulting solid was recrystallized from CH₂Cl₂-hexane to givethe, title compound (0.01° g, 5.6% yield).

[0836] mp: 153-155° C.

[0837]¹H-NMR (CDCl₃) δ: 7.85 (d, J=9 Hz. 2H), 7.54 (d. J=8 Hz, 2H), 7.45(s, 1H), 7.26 (d. J=9 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 6.76 (s,1H)_(t 6.62) (d, J=3 Hz, 1H); 6.46 (dd, J=3, 2 Hz, 1H), 6.34 (d, J=2 Hz,1H), 4.84 (brs, 2H), 2.19 (s, 3H).

[0838] mS (EI): m/z 378 (M⁺)

Example 55

[0839]1-[4-(3-Furyl)phenyl]-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0840]1-[4-(3-Furyl)phenyl-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole.

[0841] To a stirred solution of1-(4-bromophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (0.08g, 0.2 mmol) in DME (2.5 mL) was added furan-3-boronic acid (0.027 g,0.24 mmol), bis(triphenylphosphine)palladium(II)chloride (0.016 g, 0.02mmol) and saturated NaHCO₃ solution (0.8 mL) at room temperature undernitrogen. The mixture was heated at reflux temperature for 4 hours, andcooled down to room temperature. The reaction mixture was filteredthrough celite, the filtrate was poured into water and the whole wasextracted with ethyl acetate (10 mL×3). The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by thin-layer chromatography eluting with hexane/ethylacetate (3/1). The resulting solid was recrystallized from CH₂Cl₂-hexaneto give the title compound (0.01 g, 13.3% yield).

[0842] mp: 154-156° C.

[0843]¹H-NMR (CDCl₃) δ: 7.76-7.73 (m, 3H), 7.50-7.49 (m, 1H), 7.46 (d,J=8 Hz, 2H), 7.29 (d, J=9 Hz, 2H), 7.13 (d, J=9 Hz, 2H), 6.80 (s, 1H),6.70 (s, 1H), 6.43 (d, J=1 Hz, 1H), 3.03 (s, 3H), 2.19 (s, 3H).

[0844] Anal. Calcd. for. C₂₂H₁₉NO₃S: C, 70.00; H, 5.07; N, 3.71. Found:C, 69.72; H, 5.39; N, 3.51.

[0845] mS (EI): m/z 377 (M⁺)

Example 56

[0846]2-[4-(3-Furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0847] The title compound was prepared according to the procedure ofExample 55 using2-(4-bromophenyl)-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole.

[0848] mp: 193-195° C.

[0849]¹H-NMR (CDCl₃) δ: 7.87 (d, J=9 Hz, 2H), 7.72 (s, 1H), 7.47 (s,1H), 7.37 (d, J=8 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.11 (d, J=8 Hz, 2H),6.77 (m, 1H). 6.68 (m, 1H), 6.35 (m, 1H), 3.08 (s, 3H), 2.19 (s, 3H).

[0850] Anal. Calcd. for. C₂₂H₁₉NO₃S, 1.0H₂O: C, 66.82; H, 5.35; N, 3.54.Found: C, 66.65; H, 5.18; N, 3.60.

[0851] mS (EI): m/z 377 (M⁺)

Example 57

[0852] 2-Biphenyl-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0853] The title compound was prepared according to the procedure ofExample 55 using2-(4-bromophenyl)-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole, andphenylboronic acid, instead of furan-3-boronic acid.

[0854]¹H-NMR (CDCl₃) δ: 7.88 (d, J=9 Hz, 2H), 7.58 (d, J=8 Hz, 2H), 7.49(d, J=8 Hz, 2H), 7.46-7.40 (m, 2H), 7.36-7.31 (m, 3H), 7.17 (d, J=8 Hz,2H), 6.78 (s, 1H), 6.37 (d, J=2 Hz, 1H), 3.07 (s, 3H), 2.20 (s, 3H).

[0855] mS (EI): m/z 387 (M⁺)

Example 58

[0856]1-[4-(2-Furyl)phenyl]-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0857]1-[4-(2-Furyl)phenyl]-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole.

[0858] To a stirred solution of1-(4-bromophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (0.1g, 0.26 mmol) in dioxane (5 mL) was added 2-(tributylstannyl)furan(0.118 g, 0.33 mmol), LiCl (0.027 g, 0.64 mmol),tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 0.5 hours. After cooling, volatiles were removed by evaporation. Theresidue was purified by flash chromatography eluting with hexane/ethylacetate (4/1). The resulting solid was recrystallized from CH₂Cl₂/hexaneto give the title compound (0.026 g, 26.5% yield).

[0859] mp: 133-135° C.

[0860]¹H-NMR (CDCl₃) δ: 7.74 (d, J=9 Hz, 2H), 7.64 (d, J=9 Hz, 2H), 7.48(dd, J=2, 1 Hz, 1H), 7.29 (d, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 6.80(m? 1H), 6.67 (d J=3 Hz, 1H), 6.49 (dd, J=3;2 Hz, 1H), 6.43 (d, J=2 Hz,1H), 3.03 (s. 3H), 2.19 (s, 3H).

[0861] Anal. Calcd. for. C₂₂H₁₉NO₃S, 0.8H₂O: C, 67.43: H, 5.30; N, 3.57.Found: C, 67.21; H, 5.39; N, 3.96.

[0862] mS (EI): m/z 377 (M⁺)

Example 59

[0863]2-[4-(2-Furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole

[0864] The title compound was prepared according to the procedure ofExample 58 using2-(4-bromophenyl)-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole.

[0865] mp: 193-194° C.

[0866]¹H-NMR (CDCl₃) δ: 7.87 (d, J=9 Hz, 2H), 7.55 (d, J=9 Hz. 2H), 7.45(d, J=2 Hz, 1H), 7.31 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 6.77 (s,1H), 6.63 (d, J=3 Hz, 1H), 6.45 (dd, J=3, 2 Hz, 1H), 6.35 (d, J=2 Hz,1H), 3.07 (s, 3H), 2.19 (s, 3H).

[0867] Anal. Calcd. for. C₂₂H₁₉NO₃S 1.2H₂O: C, 66.21; H, 5.40; N, 3.51.Found: C, 66.08; H, 5.01; N, 3.89.

[0868] mS (EI): m/z 377 (M⁺)

Example 60

[0869]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[0870] 4,4,4-Trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione. (Step 1)

[0871] To a stirred solution of4,4,4-trifluoro-]-(4-bromophenyl)butane-1,3-dione (1 g, 3.39 mmol,prepared according to the method of J. Med. Chem., 1997, 40, 1347) inDME (40 mL) was added furan-2-boronic acid (0.455 g, 4.07 mmol),bis(triphenylphosphine) palladium(II)chloride (0.271 g, 0.386 mmol) andsaturated NaHCO₃ solution (12 mL) at room temperature under nitrogen.The mixture was heated at reflux temperature for 5 hours, and cooleddown to room temperature. The reaction mixture was filtered throughcelite, the filtrate was poured into water and the whole was extractedwith ethyl acetate (30 mL×3). The organic layer was washed with brine,dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by flash chromatography eluting with hexane/ethyl acetate (3/1)to give the subtitle compound (0.586 g, 61.2% yield).

[0872] mS (EI): m/z 282 (M⁺)

[0873]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.(Step 2)

[0874] 3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride (0.188g, 0.78 mmol) was added to a solution of4,4,4-Trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione (0.2 g, 0.71 mmol)in EtOH (15 mL). The mixture was heated at reflux temperature for 17hours and cooled down to room temperature. The reaction mixture wasconcentrated in vacuo, and the residue was taken up in ethyl acetate,washed with water and brine, dried over sodium sulfate, and concentratedin vacuo. The residue was purified by flash chromatography eluting withhexane/ethyl acetate (3/1). The resulting solid was recrystallized fromethyl acetate/hexane to give the title compound (0.185 g, 58.0% yield).

[0875] mp: 129-130° C.

[0876]¹H-NMR (CDCl₃) δ: 7.92 (dd, J=9, 8 Hz, 1H), 7.71 (d, J=9 Hz, 2H),7.52 (dd, J=2, 1 Hz, 1H), 7.42 (dd, J=2, 10 Hz, 1H), 7.27 (d, J=8 Hz,2H), 7.23 (d, J=2 Hz, 1H), 6.81 (s,]1H), 6.76 (d, J=3 Hz, 1H), 6.52 (dd,J=3, 2 Hz, 1H), 3.23 (s, 3H).

[0877] Anal. Calcd. for. C₂₁H₁₄F₄N₂O₃S, 0.1hexane: C, 56.34; H, 3.31; N,6.14. Found: C, 56.34; H; 3.55; N, 5.79.

[0878] mS (EI): m/z 450 (M⁺)

[0879] 3-Fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride wasprepared as follows:

[0880] 3-Fluoro-4-(methylsulfonyl)nitrobenzene

[0881] A mixture of 3,4-difluoronitrobenzene (10 g, 62.9 mmol) andsodium methanesulfinate (8.3 g, 69.1 mmol) in DMSO (60 mL) was heated at130° C. for 8 hours. After cooling down to room temperature, the mixturewas poured into ice-water. The whole was extracted with ethyl acetate(200 mL×2), the combined organic layer washed with water (80 mL), brine(80 mL), dried over MgSO₄, and concentrated in vacuo. The residue wascrystallized from hexane and triturated with hexane to give the subtitlecompound (10.2 g, 74% yield).

[0882]¹H-NMR (CDCl₃) δ: 8.25-8.10 (m, 3H), 3.29 (s, 3H).

[0883] mS (EI) 219 (M⁺).

[0884] 3-Fluoro-4-(methylsulfonyl)aniline

[0885] A mixture of 3-fluoro-4-(methylsulfonyl)nitrobenzene (8 g, 36.5mmol), iron powder (22 g, 394 mmol), and acetic acid (0.3 mL) in water(200 mL) was heated at 95° C. for 3 hours. After cooling, insolubleswere filtered off by Celite. The filtrate was extracted with ethylacetate (200 mL×2), the combined organic layer washed with water, brine,dried over MgSO₄, and concentrated in vacuo. Chromatographicpurification of the residue eluting with ethyl acetate/hexane (1/1)provided the subtitle compound (6.2 g, 90% yield).

[0886]¹H-NMR (CDCl₃) δ: 7.65 (t, J=8.2 Hz, 1H), 6.46 (dd, J=8.6, 2.3 Hz,1H), 6.40 (dd, J=12, 2.3 Hz, 1H), 4.37 (br.s, 2H), 3.15 (s, 3H).

[0887] 3-Fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride

[0888] To a stirred suspension of 3-fluoro-4-(methylsulfonyl)aniline(8.1 g, 42.9 mmol) in 20% aqueous HCl (27 mL) was added dropwise asolution of sodium nitrite (3 g, 43.5 mmol) in water (20 mL) at 0° C.After stirring for 1 hour, the resulting suspension was added to asolution of sodium sulfite (13.5 g, 110 mmol) in water (60 mL) and 20%aqueous NaOH (3 mL) at 0-5° C. Then the mixture was heated at 60-70° C.for 2 hours, and conc. HCl (3.5 mL) was added. The resulting mixture washeated for further 5 hours at 60° C. After cooling down to roomtemperature, the mixture was made basic by Na₂CO₃. The whole wasextracted with THF (150 mL×3), the combined organic layer washed withbrine (100 mL), dried over MgSO₄, and concentarted in vacuo. Theresulting solid was recrystallized from EtOH to give3-fluoro-4-(methylsulfonyl)phenylhydrazine (5 g, 57% yield).

[0889]¹H-NMR (CDCl₃) δ: 7.64 (t, J=8.7 Hz, 1H), 6.67 (dd, J=12.9, 2.2Hz, 1H), 6.56 (dd, J=8.7, 2.2 Hz, 1H), 5.85 (br.s, 1H), 3.72 (br.s, 2H),3.15 (s, 3H).

[0890] The solid (5 g) was dissolved in 10% methanolic HCl (30 mL), andvolatiles were removed by evaporation. The residue was recrystallizedfrom MeOH to give the title compound (4.66 g).

[0891]¹H-NMR (DMSO-d₆) δ: 10.65 (br.s), 9.42 (br.s, 1H), 7.70 (t, J=8.2Hz, 1H), 7.10-6.86 (m, 2H), 3.24 (s, 3H).

Example 61

[0892]1-[4-(Fluoromethylsulfonyl)phenyl]]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[0893] [4-(Fluoromethylsulfonyl)phenyl]hydrazine hydrochloride. (Step 1)

[0894] A mixture of 4-chlorophenyl fluoromethyl sulfone (1.97 g, 9.44mmol, prepared according to the method of Ukrainskill KhimicheskillZhurnal, 1972, 38, 1034) and hydrazine anhydrous (1.84 g, 57.5 mmol) inDMF (30 mL) was heated to 120° C. for 16 hours, and cooled down to roomtemperature. The reaction mixture was poured into water (150 mL) and thewhole was extracted with ethyl acetate/hexane/ether (2/1/1, 60 mL×3).The organic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The resulting solid (1.56 g, 7.64 mmol) was addedHCl-MeOH reagent 10 (10 mL) at room temperature and stirred for 10minutes. The mixture was concentrated in vacuo to give the subtitlecompound (0.91 g, 49.4% yield).

[0895] mS (EI): m/z 204 (M⁺)

[0896]1-[4-(Fluoromethylsulfonyl)phenyl]]-5-[4-(2-furl)phenyl]-3-(trifluoromethyl-1H-pyrazole.(Step 2)

[0897] [4-(fluoromethylsulfonyl)phenyl]hydrazine hydrochloride (0.481 g,2 mmol) was added to a solution of4,4,4-Trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione (0.564 g, 2 mmol)in EtOH (15 mL). The mixture was heated at reflux temperature for 4.5hours and cooled down to room temperature. The reaction mixture wasconcentrated in vacuo, and the residue was taken up in ethyl acetate,washed with water and brine, dried over sodium sulfate, and concentratedin vacuo. The residue was purified by flash chromatography eluting withhexane/ethyl acetate (3/1). The resulting solid was recrystallized frommethylene chloride/hexane to give the title compound (0.14 g, 15.5%yield).

[0898] mp: 149-152° C.

[0899]¹H-NMR (CDCl₃) δ: 7.97 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 2H), 7.61(d, J=9 Hz, 2H), 7.51 (d, J=1 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 6.82 (s,1H), 6.74 (d, J=3 Hz, 1H), 6.51 (dd, J=3, 2 Hz, 1H), 5.14 (d, J=47 Hz,2H).

[0900] Anal. Calcd. for. C₂₁H₁₄F₄N₂O₃S, 1H₂O, 0.1hexane: C, 54.20; H,3.61; N, 5.91. Found: C, 54.24; H, 3.32; N, 5.55.

[0901] mS (EI): m/z 450 (M⁺)

Example 62

[0902]4-[5-[4-(2-Furyl)phenyl]-4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole

[0903]4-[5-[4-Bromophenyl]-4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 1)

[0904] The subtitle compound was prepared according to the procedure ofExample 1 using 2-(4-Bromobenzoyl)-3-(dimethylamino)acrylonitrile(prepared according to the method of patent No.# DE 2330913) instead of4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione in step 1.

[0905]¹H-NMR (CDCl₃) δ: 8.07 (s, 1H), 7.98 (ddd, J=9, 2, 2 Hz, 2H), 7.61(ddd, J=9, 2, 2 Hz, 2H), 7.50 (ddd, J=9, 2, 2 Hz, 2H), 7.21 (ddd, J=9,2, 2 Hz, 2H), 3.09 (s, 3H).

[0906]4-[5-[4-(2-Furyl)phenyl]-4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 2)

[0907] The title compound was prepared according to the procedure ofExample 1 using 2-furanboronic acid instead of thiophen-3-boronic acidand 4-[5-[4-Bromophenyl]4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazoleinstead of1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazolein step 2.

[0908] mp: 229-230° C.

[0909]¹H-NMR (CDCl₃) δ: 8.07 (s, 1H), 7.96 (d, J=8 Hz, 2H), 7.74 (d, J=8Hz, 2H), 7.55-7.51 (m, 3H), 7.34 (d, J=8 Hz, 2H), 6.77 (d. J=3 Hz, 1H),6.53-6.50 (m, 1H), 3.73 (s, 3H).

[0910] Anal. Calcd. for: C₂₁H₁₅N₃O₃S ⅓H₂O: C, 63.79H, 3.99; N, 10.63.Found: C, 63.77; H, 4.04; N, 10.55.

Example 63

[0911]4-[5-[4-(2-Furyl)phenyl]-3-hydroxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole

[0912] Ethyl5-(4-Bromophenyl)-1-[4-(methylsulphonyl)phenyl]-1H-pyrrazole-3-carboxylate.(Step 1)

[0913] The subtitle compound was prepared according to the procedure ofExample 1 using Ethyl 4-(4-bromophenyl)-2,4-diketobutyrate (preparedaccording to the method of J. Med. Chem., 1997, 40, 1347) instead of4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione in step 1.

[0914]¹H-NMR (CDCl₃) δ: 7.936 (ddd, J=9, 2, 2 Hz, 2H), 7.58-7.49 (m,4H), 7.10 (ddd, J=9, 2, 2 Hz, 2H), 7.06 (s, 1H), 4.66 (q, J=7 Hz 2H),3.07 (s, 3H), 1.43 (t, J=7 Hz 3H).

[0915]4-[5-(4-Bromophenyl)-3-hydroxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 2)

[0916] The subtitle compound was prepared according to the procedure ofExample 18 using Ethyl5-(4-Bromophenyl-1-[4-(methylsulphonyl)phenyl]-1H-pyrrazole-3-carboxylateinstead of Methyl5-(4-Bromophenyl)-1-[4-sulfamoylphenyl]-1H-pyrrazole-3-carboxylate instep 1.

[0917]¹H-NMR (CDCl₃) δ: 7.92 (d, J=8 Hz, 2H), 7.52-7.46 (m, 4H), 7.11(d, J=8 Hz, 2H), 6.56 (s, 1H), 4.80 (br, 2H), 3.07 (s, 3H), 2.10 (br,1H).

[0918]4-[5-[4-(2-Furyl)phenyl]-3-hydroxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 3)

[0919] The title compound was prepared according to the procedure ofExample 1 using 2-furanboronic acid instead of 2-thiophenboronic acidacid and4-[5-[4-Bromophenyl]-3-hydroxymethyl-[4-(methylsulfonyl)phenyl]-1H-pyrazoleinstead of1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazolein step 2.

[0920] mp: 175.5-176° C.

[0921]¹H-NMR (CDCl₃) δ: 7.90 (ddd, J=9, 2, 2 Hz, 2H), 7.66 (ddd, J=9, 2,2 Hz, 2H), 7.53 (ddd, J=9, 2, 2 Hz, 2H), 7.50 (dd, J=2, 1 Hz, 1H),7.26-7.23 (2H), 6.71 (dd, J=3, 1 Hz, 1H), 6.58 (s, 1H), 6.50 (dd, J=3, 2Hz, 1H), 4.81 (d, J=6 Hz, 2H), 3.06 (s, 3H) 2.09 (t, J=6 Hz, 1H).

[0922] Anal. Calcd. for: C₂₁H₁₈N₂O₄S₁: C, 63.95H, 4.60; N, 7.10. Found:C, 63.67; H, 4.65; N, 7.12.

Example 64

[0923]3-Cyanomethyl-4-[5-[4-(2-furyl)phenyl]-1-14-(methylsulfonyl)phenyl]-1H-pyrazole

[0924]4-[5-[4-Bromophenyl]-3-cyanomethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 1)

[0925] The subtitle compound was prepared according to the procedure ofExample 18 using4-[5-[4-Bromophenyl]-3-hydroxymethyl-[4-(methylsulfonyl)phenyl]-1H-pyrazole(prepared according to the procedure of EXAMPLE 63, step 2) instead of4-[3-(Hydroxymethyl)-5-(4-bromophenyll)-1H-pyrazol-1-yl]-1-phenylsulfonamidein step 2 and step 3.

[0926]¹H-NMR (CDCl₃) δ: 7.94 (ddd, J=9, 2, 2 Hz, 2H), 7.52 (ddd, J=9, 2,2 Hz, 2H), 7.48 (ddd, J=9, 2, 2 Hz, 2H), 7.11 (ddd, J=9, 2, 2 Hz, 2H),6.59 (s, 1H), 3.86 (s, 2H), 3.07 (s, 3H).

[0927]3-Cyanomethyl-4-[5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 2)

[0928] The title compound was prepared according to the procedure ofExample 1 using 2-furanboronic acid instead of 2-thiophenboronic acidand4-[5-[4-Bromophenyl]-3-cyanomethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazoleinstead of1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.

[0929] mp: 193-193.5° C.

[0930]¹H-NMR (CDCl₃) δ: 7.90 (ddd, J=9, 2, 2 Hz, 2H), 7.67 (ddd, J=9, 2,2 Hz, 2H), 7.53-7.50 (m, 3H), 7.24 (ddd, J=9, 2, 2 Hz, 2H), 6.73 (d, J=3Hz, 1H), 6.62 (s, 2H), 6.50 (dd, J=3, 2 Hz, 1H), 3.87 (s, 2H), 3.07 (s,3H).

[0931] Anal. Calcd. for: C₂₂H₁₇N₃O₃S ¼H₂O: C, 64.77H, 4.32; N, 10.30.Found: C, 64.90; H, 4.40; N, 10.53.

Example 65

[0932] Ethyl5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate

[0933] The title compound was prepared according to the procedure ofExample 1 using 2-furanboronic acid instead of 2-thiophenboronic acidand Ethyl5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylateprepared according to the procedure of EXAMPLE 63, step 1) instead of1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.

[0934] mp: 180.9-181.1° C.

[0935]¹H-NMR (CDCl₃) δ: 7.94 (ddd, J=9, 2, 2 Hz, 2H), 7.67 (ddd, J=9, 2,2 Hz, 2H), 7.60 (ddd, J=9, 2, 2 Hz, 2H), 7.50 (d, J=2 Hz, 1H), 7.24(ddd, J=9, 2, 2 Hz, 2H), 7.08 (s, 1H), 6.73 (d, J=3 Hz, 1H), 6.50 (dd,J=3, 2 Hz, 1H), 4.77 (q, J=7 Hz, 2H), 3.06 (s, 3H), 1.44 (t, f-7 Hz,3H).

[0936] Anal. Calcd. for: C₂₃H₂₀N₂O₅S ½H₂O: C, 62.01H, 4.75; N, 6.29.Found: C, 62.37; H, 4.70; N, 6.38.

Example 66

[0937]5-[4-(1-Imidazolyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol

[0938] To a suspention of sodium hydride (0.04 g: 1 mmol) (60% mineraloil dispersion; washed with dry hexane (3 mL)) in DMF (2 mL) was addedimidazol (0.068 g) at room temperature and the mixture was stirred 0.30minutes. Then,4-[5-[4-Bromophenyl]-3-trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole(0.445 g) and copper powder (0.0063 g) were added and the whole washeated at 150° C. for 3 hours. After cooling, water (30 mL) was added tothe reaction mixture and the whole was extracted with CH₂Cl₂ (30 mL×2),the extract was washed with water and brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with ethyl acetate/methanol (1/0.03). The resulting solid wasrecrystallized with dichloroethane-diisopropyl ether to give the titlecompound (0.07 g).

[0939] mp: 183-184° C.

[0940]¹H-NMR (CDCl₃) δ 7.99 (d, J=9 Hz, 2H), 7.93 (br. 1H), 7.57 (d, J=9GHz, 2H), 7.45 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz. 2H), 7.34 (br, 1H),7.26 (1H), 6.85 (s, 1H), 3.08 (s, 3H).

[0941] Anal. Calcd. for C₂₀H₁₅N₄O₂F₃S: C, 55.55; H, 3.50; N, 12.96.Found: C, 55.34; H. 3.83; N, 12.89.

Example 67

[0942]5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylicacid

[0943] To a stirred solution of Ethyl5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate(prepared according to the procedure of Example 63, step 1) (0.1 g) inethanol (5 mL)-THF (3 mL) was added 2N-Sodium hydroxied solution inwater (1 mL) and the mixture was heated at reflux temperature for 1.5hours. After cooling, 2N—HCl solution (2 mL) and water (20 mL) wereadded to the mixture. The whole was extracted with CH₂Cl₂ (50 mL×2), theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The resultig solid was recrystallized with isopropanol-waterto give the title compound (0.08 g).

[0944] mp: >280° C.

[0945]¹H-NMR (DMSO-d₆) δ: 7.94 (d, J=9 Hz, 2H), 7.77 (d, J=2 Hz, 1H),7.71 (d, J=9 Hz, 2H), 7.55 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H), 7.01(d. J=3 Hz, 1H), 6.74° (s, 1H), 6.61 (dd, J=3, 2 Hz, 1H), 3.26 (s, 3H).

Example 68

[0946] 2-[4-(2-Furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene

[0947] 3-Bromo-[2-(4-methoxy)phenyl]thiophene

[0948] To a sirred suspension of 2,3-dibromothiophene (7.96 g, 0.033mmol), 4-methoxybenzeneboronic acid (5 g, 0.033 mmol), and NaHCO₃ (5 g,0.06 mmol) in DME-water-(120 mL-40 mL) was addeddichlorobis(triphenylphosphine)palladium (2.4 g, 3.3 mmol) at roomtemperature under N₂. The resulting mixture was heated at refluxtemperature for 3 hours. After cooling, volatiles were removed byevaporation. The residue was purified by flash chromatography elutingwith hexane to give the subtitle compound (4.03 g, 45% yield).

[0949]¹H-NMR (CDCl₃) δ: 7.56 (d, J=8.8 Hz, 2H), 7.22 (d, J=5.5 Hz, 1H),7.02 (d, J=5.5 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 3.84 (s, 3H).

[0950] 2-[(4-Methoxy)phenyl]-3-[(4-methylthio)phenyl]thiophene

[0951] To a sirred suspension of 3-bromo-[2-(4-methoxy)phenyl]thiophene(4.03 g, 0.015 mmol). 4-(methylthio)benzeneboronic acid (2.77 g. 0.016mmol), and NaHCO₃ (3.78 g, 0.045 mmol) in DME-water (90 mL-30 mL) wasadded dichlorobis(triphenylphosphine)palladium (1.05 g. 1.5 mmol) atroom temperature under N₂. The resulting mixture was heated at refluxtemperature for 3 hours. After cooling, volatiles were removed byevaporation. The residue was purified by flash chromatography elutingwith hexane to give the subtitle compound (3.4 g, 73% yield). ¹H-NMR(CDCl₃) δ: 7.28-7.10 (m, 8H), 6.80 (d, J=8.9 Hz, 2H), 3.80 (s, 3H), 2.48(s, 3H).

[0952] 2-[(4-Methoxy)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene

[0953] To a stirred solution of2-[(4-methoxy)phenyl]-3-[(4-methylthio)phenyl]thiophene (3.4 g, 11 mmol)in CH₂Cl₂ (50 mL) was added mCPBA (70% purity, 5.18 g, 30 mmol) at 5-10°C. After stirring for 1 hour at room temperature, the mixture was pouredinto saturated NaHCO₃ and partitioned. The organic layer was washed withbrine, dried over MNgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate/hexane (1/2)to give the subtitle compound (2.67 g, 71% yield).

[0954]¹H-NMR (CDCl₃) δ: 7.83 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H),7.33 (d, J=5.3 Hz, 1H), 7.19 (d, J=8.9 Hz, 2H), 7.15 (d, J=5.3 Hz, 1H),6.83 (d, J=8.9 Hz, 2H), 3.82 (s, 3H), 3.07 (s, 3H).

[0955] 2-[(4-Hydroxy)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene

[0956] A mixture of2-[(4-methoxy)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene (2.0 g, 5mol) and 48% hydrogen bromide (29 mL) was heated at 140° C. for 15hours. After cooling, the mixture was poured into water. The whole wasextracted with ethyl acetate (70 mL×3), the combined organic layerwashed with brine, dried over MgSO₄, and evaporated in vacuo.Chromatographic purification eluting with ethyl acetate/hexane (1/2)provided the subtitle compound (1.58 g, 82% yield).

[0957]¹H-NMR (CDCl₃) δ: 7.82 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H),7.33 (d, J=5.3 Hz, 1H), 7.17-7.10 (m, 3H), 6.76 (d, J=8.7 Hz, 2H), 3.08(s, 3H).

[0958]3-[(4-Methylsulfonyl)phenyl]-2-[(4-trifluoromethylsulfonyloxy)phenyl]-thiophene

[0959] To a stirred solution of2-[(4-hydroxy)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene (1.58 g,4.79 mmol), triethylamine (1.45 g, 14.4 mmol) in CH₂Cl₂ (100 mL) wasadded triflic anhydride (1.69 g, 5.98 mmol) at −78° C. under N₂. Afterstirring for 5 minutes at same temperature, the mixture was allowed towarm to room temperature. The mixture was poured into water, and thewhole was extracted with CH₂Cl₂ (50 mL×2). The combined organic layerwas washed with brine, dried over MgSO₄, and evaporated in vacuo.Chromatographic purification eluting with ethyl acetate/hexane (1/2)provided the subtitle compound (1.93 g, 87% yield).

[0960]¹H-NMR (CDCl₃) δ: 7.87 (d, J=8.4 Hz, 2H), 7.46-7.41 (m, 3H), 7.34(d, J=8.9 Hz, 2H), 7.21 (d, J=8.9 Hz, 2H), 7.18 (d, J=5.3 Hz, 1H), 3.08(s, 3H).

[0961] 2-[4-(2-Furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene

[0962] The title compound was prepared according to the procedure ofExample 35 using3-[(4-methylsulfonyl)phenyl]-2-[(4-trifluoromethylsulfonyloxy)phenyl]-thiopheneinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrolein step 4.

[0963] mp: 220-223° C.

[0964]¹H-NMR (CDCl₃) δ: 7.84 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H),7.51-7.46 (m, 3H), 7.38 (d, J=5.3 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.17(d, J=5.3 Hz, 1H), 6.67 (d, J=3.5 Hz, 1H), 6.48 (dd, J=3.5, 1.8 Hz, 1H),3.07 (s, 3H).

[0965] Anal. Calcd. for C₂₁H₁₆O₃S₂ 0.3H₂O: C, 65.36; H, 4.34. Found: C,65.44; H, 4.37.

Example 69

[0966] 2-[4-(3-Furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene

[0967] The title compound was prepared according to the procedure ofExample 35 using3-[(4-methylsulfonyl)phenyl]-2-[(4-trifluoromethylsulfonyloxy)phenyl]-thiopheneinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrroleand 3-furanboronic acid instead of 2-furanboronic acid in step 4.

[0968] mp: 235-237° C.

[0969]¹H-NMR (CDCl₃) δ: 7.85 (d, J=8.6 Hz, 2H), 7.75 (br.s, 1H),7.52-7.47 (m, 3H), 7.42 (d, J=8.6 Hz, 2H), 7.38 (d, J=5.3 Hz, 1H), 7.27(d, J=8.6 Hz, 2H), 7.17 (d, J=5.3 Hz, 1H), 6.70 (dd, J=2.0, 1.0 Hz, 1H),3.07 (s, 3H).

[0970] Anal. Calcd. for C₂₁H₁₆O₃S₂ 0.1H₂O: C. 65.98; H, 4.27. Found: C,65.80; H, 4.35.

Example 70

[0971]-4-[5-[3-Chloro-4-(2-furyl)phenyl]-3-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0972] 1-(4-Hydroxy-3-chlorophenyl)ethanone (Step 1)

[0973] To a stirred solution of 2-chlorophenol (10.0 g, 77.8 mmol) incarbon disulfide (20 ml) was added aluminum chloride (21.8 g, 163.4mmol) at 0° C. under nitrogen. Acetyl chloride (6.72 g, 85.6 mmol) wasadded, and the mixture was heated at reflux temperature for 6 hours. Themixture was cooled down to room temperature, and poured into ice-water.The whole was extracted with diethylether. The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo. The residue wasrecrystallized with diethylether-hexane to give the title compound (6.39g, 48% yield).

[0974]¹H-NMR (CDCl₃) δ: 7.99 (d, J=2 Hz, 1H), 7.82 (dd, J=9, 2 Hz, 1H),7.08 (d, J=9 Hz, 1H), 6.17 (s, 1H), 2.56 (s, 3H).

[0975]4-[5-[3-Chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide(Step 2)

[0976] The title compound was prepared according to the procedure ofExample 30 using 1-(4-hydroxy-3-chlorophenyl)ethanone instead of1-(4-hydroxy-3-methylphenyl)ethanone.

[0977] mp: 150-152° C.

[0978]¹H-NMR (CDCl₃) δ: 7.95 (d, J=9 Hz, 2H), 7.86 (d, J=8 Hz, 1H),7.54-7.50 (m, 3H), 7.42 (d, J=2 Hz, 1H), 7.24 (d, J=4 Hz, 1H), 7.08 (dd,J=8, 2 Hz, 1H), 6.83 (s, 1H), 6.56 (dd, J=4, 2 Hz, 1H), 4.98 (s, 2H).

[0979] Anal. Calcd. for C₂₀H₁₃ClF₃N₃O₃S: C, 51.35; H, 2.80; N, 8.98.Found: C, 51.03; H, 3.05; N, 8.75.

Example 71

[0980]1-[4-(Methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[0981] The title compound was prepared according to the procedure ofExample 70 using (4-methylsulfonyl)hydrazine hydrochloride instead of(4-sulfamoylphenyl)hydrazine hydrochloride.

[0982] mp: 143-145° C.

[0983]¹H-NMR (CDCl₃) δ: 7.99 (d. J=9 Hz, 2H), 7.88 (d, J=8 Hz. 1H). 7.59(d, J=9 Hz, 2H), 7.55 (d, =2 Hz, 1H), 7.41 (d, J=2 Hz. 1H). 7.25 (d, J=4Hz, 1H). 7.09 (dd, J=8, 2 Hz, 1H), 6.84 (s, 1H), 6.56 (dd, J=4, 2 Hz,1H), 3.08 (s, 3H).

[0984] Anal. Calcd. for C₂₁H₁₄ClF₃N₂O₃S ¼Hexane: C, 55.33; H, 3.61; N,5.74. Found: C, 55.57; H, 3.58; N, 5.55.

Example 72

[0985]4-[5-[4-(2-Furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[0986] The title compound was prepared according to the procedure ofExample 30 using 1-(4-hydroxy-3-methoxyphenyl)ethanone instead of1-(4-hydroxy-3-methylphenyl)ethanone.

[0987] mp: 161-163° C.

[0988]¹H-NMR (CDCl₃) δ: 7.91 (d, J=9 Hz, 2H), 7.83 (d, J=8 Hz, 1H),7.53-7.47 (m, 3H), 7.00 (d, J=3 Hz, 1H), 6.87-6.78 (m, 3H), 6.50 (dd,J=4, 2 Hz, 1H), 4.98 (s, 2H), 3.79 (s, 3H).

[0989] Anal. Calcd. for C₂₁H₁₆F₃N₃O₄S ⅕H₂O: C, 54.01; H, 3.54; N, 9.00.Found: C, 53.80; H, 3.68; N, 8.94.

Example 73

[0990]4-[5-[3-Fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazzol-1-yl]-1-phenylsulfonamide

[0991] The title compound was prepared according to the procedure ofExample 70 using 2-fluorophenol instead of 2-chlorophenol.

[0992] mp: 166-168° C.

[0993]¹H-NMR (CDCl₃) δ: 7.95 (d, J=9 Hz, 2H), 7.86-7.80 (m, 1H),7.53-7.50 (m, 3H), 7.04 (d, J=11 Hz, 2H), 6.94-6.91 (m, 1H), 6.82 (s,1H), 6.55 (dd, J=4, 2 Hz, 1H), 4.92 (s, 2H).

[0994] Anal. Calcd. for C₂₀H₁₃F₄N₃O₃S {fraction (1/10)}H₂O: C, 53.01; H,2.94; N, 9.27. Found: C, 52.62; H, 2.92; N, 9.12.

Example 74

[0995]1-[4-(Methylsulfonyl)phenyl]-5-[3-fluor-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[0996] The title compound was prepared according to the procedure ofExample 73 using (4-methylsulfonyl)hydrazine hydrochloride instead of(4-sulfamoylphenyl)hydrazine hydrochloride.

[0997] mp: 183-185° C.

[0998]¹H-NMR (CDCl₃) δ: 7.98 (d, J=9 Hz, 2H), 7.87-7.81 (m, 1H), 7.58(d, J=9 Hz, 2H), 7.54 (d, J=2 Hz, 1H), 7.07-7.05 (m, 1H), 7.02 (s, 1H),6.94-6.91 (m, 1H), 6.83 (s, 1H), 6.55 (dd, J=4, 2 Hz, 1H), 3.08 (s, 3H).

[0999] Anal. Calcd. for C₂₁H₁₄F₄N₂O₃S: C, 56.00; H, 3.13; N, 6.22.Found: C, 55.81; H, 3.23; N, 6.11.

Example 75

[1000]4-[5-14-(5-Oxazolyl)phenyl]3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide

[1001] 2-(4-Formylphenyl)-2-methyl-1,3-dioxolane (Step 1)

[1002] To a stirred solution of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane(2.0 g, 8.23 mmol) in THF (7 ml) was added n-BuLi (1.61 M solution inhexane, 5.47 ml, 8.8 mmol) at −78° C. under nitrogen, and the mixturewas stirred for 2 hour, then allowed to warm up to 0° C. for 30 min. Asolution of 1-formylpiperidine (930 mg, 8.23 mmol) in THF (5 ml) wasadded, and the mixture was stirred for 2 hours. The mixture was madeneutral by addition of 1N HCl solution, and the whole was extracted withdiethylether. The organic layer was washed with saturated NaHCO₃ aqueoussolution, brine, dried over MgSO₄, and concentrated in vacuo. Thecompound was used for next reaction without purification.

[1003]¹H-NMR (CDCl₃) δ: 10.02 (s, 1H), 7.87 (d, J=8 Hz, 2H), 7.66 (d,J=8 Hz, 2H), 4.11-3.75 (m, 4H), 1.66 (s, 3H).

[1004] 2-[4-(5-Oxazolyl)phenyl]-2-methyl-1,3-dioxolane (Step 2)

[1005] To a stirred solution of2-(4-formylphenyl)-2-methyl-1,3-dioxolane (1.58 g, 8.23 mmol) inmethanol (10 ml) was added tosylmethyl isocyanide (2.0 g, 10.3 mmol),potassium carbonate (1.42 g, 10.3 mmol), and the mixture was heated atreflux temperature for 2 hours. The reaction mixture was diluted withwater and the whole was extracted with CH₂Cl₂. The organic layer waswashed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:4) to give the title compound (711 mg, 37% yield).

[1006]¹H-NMR (CDCl₃) δ 7.92 (s, 1H). 7.64 (d, J=8 Hz. 2H), 7.55 (d, J=8Hz, 2H), 7.36 (s, 1H), 4.09-3.77 (m, 4H), 1.67 (s, 3H).

[1007] 1-[4-(5-Oxazolyl)phenyl]ethanone (Step 3)

[1008] To a stirred solution of2-[4-(5-oxazolyl)phenyl]-2-methyl-1,3-dioxolane (711 mg, 3.08 mmol) inacetone (18 ml) and water (2.8 ml) was added pyridiniump-toluenesulfonate (116 mg, 0.46 mmol), and the mixture was heated atreflux temperature for 8 hours. The mixture was cooled down to roomtemperature, and concentrated in vacuo. The residue was dissolved indiethylether and washed with saturated NaHCO₃ aqueous solution, brine,dried over MgSO₄, and concentrated in vacuo. The compound was used fornext reaction without purification.

[1009]¹H-NMR (CDCl₃) δ 8.03 (d, J=9 Hz. 2H), 7.98 (s, 1H), 7.75 (d, J=9Hz, 2H), 7.49 (s, 1H), 2.63 (s, 3H).

[1010]4-[5-[4-(5-Oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide(Step 4)

[1011] The title compound was prepared according to the procedure ofExample 30 using 1-[4-(5-oxazolyl)phenyl]ethanone instead of1-[4-(2-furyl)-3-methylphenyl]ethanone.

[1012] mp: 128-130° C.

[1013]¹H-NMR (DMSO-d₆) δ: 8.48 (s, 1H), 7.89 (d, J=8 Hz, 2H), 7.77 (d,J=8 Hz, 2H), 7.79 (s, 1H), 7.59 (d, J=8 Hz, 2H), 7.51 (s, 2H), 7.43 (d,J=8 Hz, 2H), 7.32 (s, 1H).

[1014] Anal. Calcd. for C₁₉H₁₃F₃N₄O₃S 0.56 Dichloromethane: C, 48.75; H,2.95; N, 11.62. Found: C, 47.35; H, 3.28; N, 10.66.

Example 76

[1015]1-[4-(Methylsulfonyl)phenyl]-5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1016] The title compound was prepared according to the procedure ofExample 75 using (4-methylsulfonyl)hydrazine hydrochloride instead of(4-sulfamoylphenyl)hydrazine hydrochloride.

[1017] mp: 178-180° C.

[1018]¹H-NMR (CDCl₃) δ: 7.98 (s, 1H), 7.97 (d, J=8 Hz, 2H), 7.70 (d, J=8Hz, 2H), 7.58 (d, J=8 Hz, 2H), 7.44 (s, 1H), 7.33 (d, J=8 Hz. 2H). 6.87(s, 1H). 3.09 (s, 3H).

[1019] Anal. Calcd. for C₂₀H₁₄F₃N₃O₃S ⅕H₂O: C, 54.97: H, 3.32; N, 9.62.Found: C, 54.64; H, 3.48; N, 9.61.

Example 77

[1020]4-[5-14-(2-Furyl)-2-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide

[1021] Trifluoromethanesulfonic acid 4-acetyl-3-methylphenyl ester (Step1)

[1022] To a stirred solution of 1-(4-hydroxy-2-methylphenyl)ethanone(0.939 g, 6.25 mmol) in dichloromethane (37.5 ml) was added lutidine(0.804 g, 7.5 mmol), 4-dimethylaminopyridine (0.153 g, 1.25 mmol),trifluoromethanesulfonic anhydride (2.11 g, 7.5 mmol) at −30° C. undernitrogen, and the mixture was stirred for 1 hour, and then allowed towarm up to room temperature for 2 hours. The reaction mixture wasdiluted with water and the whole was extracted with dichloromethane. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo to give 1.76 g of brown oil. The compound was used for nextreaction without purification.

[1023] 1-[4-(2-Furyl)-2-methylphenyl]ethanone (Step 2)

[1024] To a stirred solution of trifluoromethanesulfonic acid4-acetyl-3-methylphenyl ester (1.76 g, 6.25 mmol) in dioxane (60 ml) wasadded 2-(tributylstannyl)furan (2.68 g, 7.5 mmol), lithium chloride(0.66 g, 15.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.722g, 0.62 mmol) under nitrogen. The mixture was heated at refluxtemperature for 2 hours, and cooled down to room temperature. Thereaction mixture was diluted with water and the whole was extracted withdiethylether. The organic layer was washed with saturated potassiumfluoride aqueous solution, brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography eluting withethyl acetate-hexane (1:10) to give title compound (1.15 g, 92%).

[1025]¹H-NMR (CDCl₃) δ: 7.75 (d, J=9 Hz, 1H), 7.57-7.51 (m, 3H), 6.76(d, J=4 Hz, 1H), 6.50 (dd, J=4, 2 Hz, 1H), 2.59 (s, 3H), 2.58 (s, 3H).

[1026] 4,4,4-Trifluoro-1-[4-(2-furyl)-2-methylphenyl]butane-1,3-dione(Step 3)

[1027] To a stirred solution of ethyl trifluoroacetate (9.90 g, 6.31mmol) in t-butylmethylether (3 ml) was added sodium methoxide (28 wt. %solution in methanol, 1.5 ml, 6.23 mmol) over 2 min. A solution of1-[4-(2-furyl)-2-methylphenyl]ethanone (1.15 g. 5.74 mmol) int-butylmethylether (4 ml) was added dropwise over 5 min. and the mixturewas stirred for 20 hours. 2N HCl (10 ml) was added, and the whole wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo to give 1.78 g of brown oil.The compound was used for next reaction without purification.

[1028]4-[5-[4-(2-Furyl)-2-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide(Step 4)

[1029] To a stirred solution of4,4,4-trifluoro-1-[4-(2-furyl)-2-methylphenyl]butane-1,3-dione (0.796 g,2.69 mmol) in ethanol (31 ml) was added (4-sulfamoylphenyl)hydrazinehydrochloride (0.66 g, 2.96 mmol), and the mixture was heated at refluxtemperature for 16 hours. The mixture was cooled down to roomtemperature, and concentrated in vacuo. The residue was dissolved inethyl acetate, washed with brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography eluting withethyl acetate-hexane (1:3). The resulting solid was recrystallized withdiisopropylether-hexane to give the title compound (0.26 g, 22% yield).

[1030] mp: 135-137° C.

[1031]¹H-NMR (CDCl₃) δ 7.83 (d, J=9 Hz, 2H), 7.55-7.42 (m, 5H), 7.21 (d,J=9 Hz, 1H), 6.73-6.71 (m, 2H), 6.50 (dd, J=4, 2 Hz, 1H), 4.91 (s, 2H),2.04 (s, 3H).

[1032] Anal. Calcd. for C₂₁H₁₆F₃N₃O₃S: C, 56.37; H, 3.60; N, 9.39.Found: C, 56.13; H, 3.64; N, 9.23.

Example 78

[1033]1-4-(Methylsulfonyl)phenyl]-5-[4-(2-furyl)-2-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole

[1034] The title compound was prepared according to the procedure ofExample 77 (step 4) using (4-methylsulfonyl)hydrazine hydrochlorideinstead of (4-sulfamoylphenyl)hydrazine hydrochloride.

[1035] mp: 175-177° C.

[1036]¹H-NMR (CDCl₃) δ: 7.88 (d, J=9 Hz, 2H), 7.57-7.49 (m, 5H), 7.22(d, J=9 Hz, 1H), 0.74-6.73 (m, 2H), 6.51 (dd, J=4, 2 Hz, 1H), 3.03 (s,3H), 2.05 (s, 3H).

[1037] Anal. Calcd. for C₂₂H₁₇F₃N₂O₃S: C, 59.19; H, 3.84; N. 6.27.Found: C, 59.04; H. 3.78; N, 6.18.

Example 79

[1038]4-[5-[2-Fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide

[1039] 1-(2-Fluoro-4-hydroxyphenyl)ethanone (Step 1)

[1040] To a stirred suspension of aluminum chloride (41.6 g, 312 mmol)in 1,2-dichloroethane (100 ml) was added 3-fluorophenol (30.95 g, 276mmol) dropwise at 0° C. Acetyl chloride (24.0 g, 306 mmol) was addeddropwise, and the mixture was heated at reflux temperature for 6 hours.The mixture was cooled down to room temperature, and poured into ice.The whole was extracted with diethylether. The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo. The residue wasrecrystallized with hexane to give the title compound (3.57 g, 8%yield). ¹H-NMR (CDCl₃) δ: 7.88-7.82 (m, 1H), 6.74 (dd, J=92 Hz, 1H),6.64 (dd, J=13, 2 Hz, 1H), 2.62 (d, J=5 Hz, 3H).

[1041]4-[5-[2-Fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl-1-phenylsulfonamide(Step 2)

[1042] The title compound was prepared according to the procedure ofExample 77 (step 4) using 1-(2-fluoro-4-hydroxyphenyl)ethanone insteadof 1-(4-hydroxy-2-methylphenyl)ethanone.

[1043] mp: 203-205° C.

[1044]¹H-NMR (CDCl₃) δ: 7.92 (d, J=9 Hz, 2H), 7.52-7.47 (m, 4H), 7.38(dd, J=11.2 Hz, 1H), 7.28-7.22 (m, 1H), 6.86 (s, 1H), 6.76 (d, J=4 Hz,1H). 6.52 (dd, J=4, 2 Hz, 1H), 4.89 (s, 2H).

[1045] Anal. Calcd. for C₂₀H₁₃F₄N₃O₃S: C, 53.22; H, 2.90; N, 9.31.Found: C, 53.05; H, 3.03; N, 9.39.

Example 80

[1046]1-[4-(Methylsulfonyl)phenyl-5-[2-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1047] The title compound was prepared according to the procedure ofExample 79 (step 4) using (4-methylsulfonyl)hydrazine hydrochlorideinstead of (4-sulfamoylphenyl)hydrazine hydrochloride.

[1048] mp: 223-225° C.

[1049]¹H-NMR (DMSO-d₆) δ: 8.01 (d, J=9 Hz, 2H), 7.83 (d, J=1 Hz, 1H),7.67-7.64 (m, 3H), 7.60-7.52 (m, 2H), 7.35 (s, 1H), 7.18 (d, J=4 Hz,1H), 6.66 (dd, J=, 2 Hz, 1H), 3.33 (s, 3H).

[1050] Anal. Calcd. for C₂₁H₁₄F₄N₂O₃S: C, 56.00; H, 3.13. N, 6.22.Found: C, 55.67; H, 3.37; N, 6.16.

Example 81

[1051]1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazole

[1052] The title compound was prepared according to the procedure ofExample 72 using (4-methylsulfonyl)hydrazine hydrochloride instead of(4-sulfamoylphenyl)hydrazine hydrochloride.

[1053] mp: 138-140° C.

[1054]¹H-NMR (CDCl₃) δ: 7.96 (d, J=9 Hz, 2H), 7.84 (d, J=8 Hz, 1H), 7.59(d, J=9 Hz, 2H), 7.49-7.48 (m, 1H), 7.01 (d, J=4 Hz, 1H), 6.86 (dd, J=8,2 Hz, 1H), 6.83 (s, 1H), 6.79 (d, J=2 Hz, 1H), 6.51 (dd, J=4, 2 Hz, 1H),3.80 (s, 3H), 3.06 (s, 3H).

[1055] Anal. Calcd. for C₂₂H₁₇F₃N₂O₄S: C, 57.14; H, 3.71; N, 6.06.Found: C, 56.75; H. 4.04; N, 5.85.

Example 82

[1056]1-[4-(Methylsulfonyl)phenyl]-5-[4-(4-thiazoyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1057] 1-(4-Acetylphenyl-2-bromo-1-ethanone (Step 1)

[1058] To a stirred solution of 1,4-diacetylbenzene (5.3 g, 32.7 mmol),aluminum chloride (0.05 g, 0.38 mmol) in diethylether (50 ml) was addedbromine (5.3 g, 32.7 mmol) dropwise over 20 minutes. The mixture wasstirred for 30 minutes, and diluted with water. The whole wasconcentrated to remove diethylether, and the aqueous suspension wasfiltered to give 7.0 g of white solid. The compound was used for nextreaction without purification.

[1059]¹H-NMR (CDCl₃) δ: 8.09-8.05 (m, 4H), 4.47 (s, 2H), 2.65 (s, 3H).

[1060] 1-[4-(4-Thiazolyl)phenyl]ethanone (Step 2)

[1061] To a stirred suspension of phosphorus pentasulfide (24.5 g, 110mmol) in dioxane (250 ml) was added formamide (28.4 g. 630 mmol), andthe mixture was heated at reflux temperature for 2 hours. The reactionmixture was cooled down to room temperature, and the solution wasdecanted away from solids. To a stirred solution of1-(4-acetylphenyl)-2-bromo-1-ethanone (2.0 g, 8.3 mmol) in dioxane (80ml) was added the thioformamide solution, and the mixture was heated atreflux temperature for 13 hours. The reaction mixture was cooled down toroom temperature, and made basic by addition of 0.5M NaOH aqueoussolution. The whole was extracted with diethylether. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:4) to give the title compound (610 mg, 36% yield).

[1062]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H). 8.04-8.02 (m, 4H), 7.69(d, J=2 Hz, 1H), 2.64 (s, 3H).

[1063] 4,4,4-Trifluoro-]-[4-(4-thiazolyl)phenyl]butane-1,3-dione (Step3)

[1064] To a stirred solution of ethyl trifluoroacetate (0.47 g, 3.3mmol) in t-butylmethylether (3 ml) was added sodium methoxide (28 wt. %solution in methanol, 0.78 ml, 3.26 mmol) over 2 min. A solution of1-[4-(4-thiazolyl)phenyl]ethanone (0.61 g, 3.0 mmol) int-butylmethylether (4 ml) was added dropwise over 5 min, and the mixturewas stirred for 20 hours. 2N HCl (10 ml) was added, and the whole wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo to give 0.54 g of brown oil.The compound was used for next reaction without purification.

[1065]1-[4-(Methylsulfonyl)phenyl]-5-[4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole(Step 4)

[1066] The title compound was prepared according to the procedure ofExample 77 using (4-methylsulfonyl)hydrazine hydrochloride instead of(4-sulfamoylphenyl)hydrazine hydrochloride.

[1067] mp: 168-170° C.

[1068]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 7.97 (d, J=8 Hz, 2H), 7.95(d, J=9 Hz, 2H), 7.63 (d, J=2 Hz, 1H), 7.58 (d, J=8 Hz, 2H), 7.32 (d,J=8 Hz, 2H), 6.84 (s, 1H), 3.07 (s, 3H).

[1069] Anal. Calcd. for C₂₀H₁₄F₃N₃O₂S₂ {fraction (1/10)}H₂O: C, 53.23;H, 3.17; N, 9.31. Found: C, 52.96; H, 3.17; N, 9.13.

Example 83

[1070]1-[3-Fluoro-4-(methylsulfonyl)phenyl-5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole

[1071] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-]-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione insteadof 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione.

[1072] mp: 123-125° C.

[1073]¹H-NMR (CDCl₃) δ: 7.94-7.88 (m, 1H), 7.75 (d, J=8 Hz, 1H), 7.55(d, J=2 Hz, 1H), 7.44 (dd, J=10, 2 Hz, 1H), 7.23-7.21 (m, 2H), 7.07 (d,J=8 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J=4 Hz, 1H), 6.54 (dd, J=3, 2 Hz,1H), 3.23 (s, 3H), 2.52 (s, 3H).

[1074] Anal. Calcd. for C₂₂H₁₆F₄N₂O₃S: C, 56.9; H, 3.47; N, 6.03. Found:C, 56.82; H, 3.61; N, 6.03.

Example 84

[1075]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-14-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1076] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-(5-oxazolyl)phenyl]butane-1,3-dione instead of4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione.

[1077] mp: 170-172° C.

[1078]¹H-NMR (CDCl₃) δ: 7.97 (s, 1H), 7.96-7.90 (m, 1H), 7.72 (d, J=9Hz, 2H), 7.46 (s, 1H), 7.42 (dd, J=10, 2 Hz, 1H), 7.33 (d, J=9 Hz, 2H),7.25-7.21 (m, 1H), 6.83 (s, 1H), 3.24 (s, 3H).

[1079] Anal. Calcd. for C₂₀H₁₃F₄N₃O₃S: C, 53.22; H, 2.90; N, 9.31.Found: C, 53.02; H, 3.16; N, 9.02.

Example 85

[1080]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1081]5-(4-Bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.(Step 1)

[1082] [3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride (0.354g, 1.47 mmol) was added to a solution of4,4,4-Trifluoro-1-(4-bromophenyl)butane-1,3-dione (0.395 g. 1.34 mmol)in EtOH (20 mL). The mixture was heated at reflux temperature for 17hours and cooled down to room temperature. The reaction mixture wasconcentrated in vacuo, and the residue was taken up in ethyl acetate,washed with water and brine, dried over sodium sulfate, and concentratedin vacuo. The residue was purified by flash chromatography eluting withhexane/ethyl acetate (3/1). The resulting solid was recrystallized fromethyl acetate/hexane to give the subtitle compound (0.537 g, 86.6%yield).

[1083] mp: 64-65° C.

[1084]¹H-NMR (CDCl₃) δ: 7.94 (dd, J=9, 8 Hz, 1H), 7.58 (d, J=9 Hz, 2H),7.39 (dd, J=10, 2 Hz, 1H), 7.21-7.18 (m, 1H), 7.14 (d, J=9 Hz, 2H), 6.79(s, 1H), 3.24 (s, 3H).

[1085] Anal. Calcd. for C₁₇H₁₁BrF₄N₂O₂S: C, 44.08; H, 2.39; N, 6.05.Found: C, 44.05; H, 2.78; N, 5.88.

[1086] mS (EI): m/z 462 (M⁺), 464 (M+2)

[1087]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.(Step 2)

[1088] To a stirred solution of5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole(0.15 g, 0.324 mmol) in DME (3.9 mL) was added furan-3-boronic acid(0.044 g, 0.389 mmol), bis(triphenylphosphine)palladium(II)chloride(0.025 g, 0.04 mmol) and saturated NaHCO₃ solution (1.3 mL) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 4 hours, and cooled down to room temperature. The reaction mixturewas filtered through celite, the filtrate was poured into water and thewhole was extracted with ethyl acetate (20 mL×3). The organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The residue was purified by flash chromatography eluting withhexane/ethyl acetate (3/1) to give the title compound (0.066 g, 45.2%yield).

[1089] mp: 74-76° C.

[1090]¹H-NMR (CDCl₃) δ: 7.93 (dd, J=9, 8 Hz, 1H), 7.80 (s, 1H),7.55-7.51 (m, 3H), 7.42 (dd, J=2, 10 Hz, 1H), 7.28-7.24 (m, 3H), 6.80(s, 1H), 6.72 (dd, J=2, 1 Hz, 1H), 3.24 (s, 3H).

[1091] Anal. Calcd. for C₂₁H₁₄F₄N₂O₃S, 0.3H₂O: C, 55.34; H, 3.23; N,6.15. Found: C, 55.39; H, 3.58; N. 6.18.

[1092] mS (EI): m/z 450 (M⁺)

Example 86

[1093]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1094] The title compound was prepared according to the procedure ofExample 85 (step 2) using thiophene-2-boronic acid, instead offuran-3-boronic acid.

[1095] mp: 75-76° C.

[1096]¹H-NMR (CDCl₃) δ: 7.94 (dd, J=9, 8 Hz, 1H), 7.66 (d, J=9 Hz, 2H),7.45-7.35 (m, 3H), 7.28-7.24 (m, 3H), 7.12 (dd, J=5, 4 Hz, 1H), 6.81 (s,1H), 3.24 (s, 3H).

[1097] Anal. Calcd. for C₂₁H₁₄F₄N₂O₂S₂, 0.05Hexane: C, 54.25; H, 3.11;N, 5.97. Found: C, 53.95; H, 3.48; N, 5.63.

[1098] mS (EI): m/z 466 (M⁺)

Example 87

[1099]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1100] The title compound was prepared according to the procedure ofExample 1 (step 2) using thiophene-3-boronic acid, instead offuran-3-boronic acid.

[1101] mp: 72-74° C.

[1102]¹H-NMR (CDCl₃) δ: 7.93 (t, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 2H),7.58-7.52 (m, 1H), 7.45-7.40 (m, 3H), 7.29 (d, J=8 Hz, 2H), 7.27-7.23(m, 1H), 6.81 (s, 1H), 3.23 (s, 3H). Anal. Calcd. for C₂₁H₁₄F₄N₂O₂S₂,0.05Hexane: C, 54.25; H, 3.11; N, 5.97. Found: C, 53.96; H, 3.46; N,5.61.

[1103] mS (EI): m/z 466 (M⁺)

Example 88

[1104] Methyl1-(4-sulfamoylphenyl)-5-[4-(2-thiazolyl)phenyl]-1H-pyrazole-3-carboxylate

[1105] The title compound was prepared according to the procedure ofExample 21 using methyl1-(4-sulfamoylphenyl)-5-(4-bromophenyl)-1H-pyrazole-3-carboxylate,instead of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide.

[1106] mp: 204-206° C.

[1107]¹H-NMR (CDCl₃) δ: 7.97 (dt, J=9, 2 Hz. 2H), 7.92 (dt, J=9, 2 Hz,2H), 7.90 (d, J=3 Hz, 1H), 7.52 (dt, J=9, 2 Hz, 2H), 7.39 (d, J=3 Hz,1H), 7.30 (ddd, J=9, 2, 2 Hz, 2H), 7.12 (s, 1H), 4.93 (br, 2H), 3.99 (s,3H).

[1108] Anal. Calcd. for C₂₀H₁₆N₄O₄S₂ ½H₂O: C, 53.44; H, 3.81; N, 12.46.Found: C, 53.43; H, 4.00; N, 12.30.

Example 89

[1109]4-[4-Cyano-5-[4-(2-thiazolyl)phenyl]-1H-pyrazol-1-yl]-1-phenylsulfonamide

[1110] The title compound was prepared according to the procedure ofExample 21 using4-[4-cyano-5-(4-bromophenyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide,instead of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide.

[1111] mp: 216-217° C.

[1112]¹H-NMR (DMSO-d₆) δ: 8.53 (s, 1H), 8.08 (d, J=9 Hz, 2H), 7.99 (d,J=3 Hz, 1H), 7.89-7.86 (m, 3H), 7.58-7.51 (m, 4H), 7.49 (br, 2H).

[1113] Anal. Calcd. for C₁₉H₁₃N₅O₂S₂: C, 56.01; H, 3.22; N, 17.19.Found: C, 55.76; H, 3.46; N, 16.88.

Example 90

[1114]4-[4-Chloro-5-[4-(2-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide

[1115]4-[4-Chloro-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide.(Step 1)

[1116] To a stirred solution of4-[5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide(0.8 g) in CH₂Cl₂ (6 mL) was added sulfuryl chloride (3 mL) at roomtemperature. The mixture was stirred for 8 hours. The reaction mixturewas poured into water and the whole was vigorously stirred 10 minutes.The resulting mixture was extracted with CH₂Cl₂ (20 mL). The organiclayer was washed with saturated NaHCO₃ solution and brine, dried oversodium sulfate, and concentrated in vacuo. The resulting solid wasrecrystallized with CH₂Cl₂-diisopropyl ether to give the title compound(0.47 g).

[1117]¹H-NMR (CDCl₃) δ: 7.93 (d, J=9 Hz, 2H), 7.59 (d, J=9 Hz, 1H), 7.41(d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 4.87 (br, 2H).

[1118]4-[4-Chloro-5-[4-(2-thiazolyl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide.(Step 2)

[1119] The title compound was prepared according to the procedure ofExample 21 using4-[4-Chloro-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide,instead of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide.

[1120] mp: 233-236° C. (decomposition)

[1121]¹H-NMR (CDCl₃) δ: 8.05 (d, J=9 Hz, 2H), 7.93-7.90 (m, 3H),7.47-7.36 (m, 5H), 4.84 (br, 2H).

[1122] Anal. Calcd. for C₁₉H₁₂N₄O₂S₂ClF₃ ⅓H₂O: C, 46.49; H, 2.60; N,11.41. Found: C, 46.86; H, 2.85; N, 11.03.

Example 91

[1123]5-[2-Fluoro-4-(2-furyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[1124] The title compound was prepared according to the procedure ofExample 79 (step 2) using 3-fluoro-4-(methylsulfonyl)phenyl hydrazinehydrochloride instead of (4-sulfamoylphenyl)hydrazine hydrochloride.

[1125] mp: 156-160° C.

[1126]¹H-NMR (DMSO-d₆) δ: 7.94 (t, J=8.1 Hz, 1H), 7.84 (br.s, 1H),7.73-7.53 (m, 4H), 7.44 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J=3.5Hz, 1H), 668-6.65 (s, 1H), 3.33 (s, 3H).

Example 92

[1127]1-[3-Fluoro-4-(methylsulfonyl)phenyl-5-[4-(2-furyl)-2-methylphenyl]-3-trifluoromethyl-]H-pyrazole

[1128] The title compound was prepared according to the procedure ofExample 77 (step 4) using 3-fluoro-4-(methylsulfonyl)phenyl hydrazinehydrochloride instead of (4-sulfamoylphenyl)hydrazine hydrochloride.

[1129] mp: 77-79° C.

[1130]¹H-NMR (DMSO-d₆) δ: 7.84 (t, J=8.2 Hz, 1H), 7.60 (s, 1H),7.58-7.50 (m, 2H), 7.41-7.34 (m, 1H), 7.25-7.15 (m, 2H), 6.73 (s, 1H),6.78-6.70 (m, 1H), 6.52 (dd, J=3.5 Hz, 1.8 Hz, 1H), 3.20 (s, 3H), 2.07(s, 3H).

Example 93

[1131]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1132] The title compound was prepared according to the procedure ofExample 60 using.4,4,4-trifluoro-1-[3-chloro-4-(2-furyl)phenyl]butane-1,3-dione insteadof 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione.

[1133] mp: amorphous.

[1134]¹H-NMR (CDCl₃) δ: 7.98-7.92 (m, 1H), 7.92 (d, J=8 Hz, 1H), 7.56(d, J=2 Hz, 1H), 7.47-7.41 (m, 2H), 7.28-7.23 (m, 2H), 7.12 (d, J=8 Hz,1H), 6.84 (s, 1H), 6.57 (dd, J=4, 2 Hz, 1H), 3.24 (s, 3H).

[1135] Anal. Calcd. for C₂₁H₁₃ClF₄N₂O₃S: C, 52.02; H, 2.70; N, 5.78.Found: C, 52.12; H, 2.79; N, 5.63.

Example 94

[1136]4-{4-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole

[1137] 4-(4-Bromophenyl)-1,3-oxazole (Step 1)

[1138] To a stirred solution, of 2,4′-dibromoacetophenone (9.66 g, 34.8mmol) in formic acid (42 ml) was added ammonium formate (7.58 g. 120.6mmol), and the mixture was heated at reflux temperature for 3 hours. Thereaction mixture was cooled down to room temperature, and made basic byaddition of 50% NaOH aqueous solution. The whole was extracted withCH₂H₂. The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with ethyl acetate-hexane (1:5) to give title compound (2.0 g,26% yield).

[1139]¹H-NMR (CDCl₃) δ: 7.95-7.93 (m, 2H), 7.62 (d, J=9 Hz, 2H), 7.53(d, J=9 Hz, 2H).

[1140] 1-[4-(1,3-Oxazol-4-yl)phenyl]-1-ethanone (Step 2)

[1141] To a stirred solution of 4-(4-bromophenyl)-11,3-oxazole (469 mg,2.09 mmol) in dioxane (20 ml) was added tributyl(1-ethoxyvinyl)tin (906mg, 2.51 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.207mmol), lithium chloride (221 mg, 5.23 mmol), and the mixture was heatedat reflux temperature for 8 hours. The reaction mixture was cooled downto room temperature, and diluted with ethyl acetate. The whole waswashed with saturated potassium fluoride aqueous solution, and theprecipitate was removed by filteration through celite. The resultingsolution was extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo. To the residuewas added THF (10 ml), 2N HCl aqueous solution (10 ml), and the mixturewas heated at reflux temperature for 8 hours. The reaction mixture wascooled down to room temperature, made neutral by addition of NaHCO₃, andextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography eluting with ethyl acetate-hexane (1:5) to givetitle compound (256 mg, 65% yield).

[1142]¹H-NMR (CDCl₃) δ: 8.06 (d, J=1 Hz, 1H), 8.01 (d, J=9 Hz. 2H), 7.98(d, J=1 Hz, 1H), 7.85 (d, J=9 Hz, 2H), 2.62 (s, 3H).

[1143] 4,4,4-Trifluoro-1-[4-(1,3-oxazol-4-yl)phenyl]-1,3-butanedione(Step 3)

[1144] To a stirred solution of 1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone(256 mg, 1.37 mmol), ethyl trifluoroacetate (214 mg, 1.51 mmol) int-butylmethylether (22 ml) was added sodium methoxide (28 wt. % solutionin methanol; 0.4 ml, 1.67 mmol) over 5 minutes, and the mixture wasstirred for 20 hours. The mixture was made neutral by addition of 2NHCl, and the whole was extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was used for next reaction without further purification. (433mg, 99% yield).

[1145]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)1phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole(Step 4)

[1146] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-(1,3-oxazol-4-yl)phenyl]-1,3-butanedione instead of4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1147] mp: 164-166° C.

[1148]¹H-NMR (CDCl₃) δ: 8.01 (d, J=15 Hz, 2H), 7.95-7.89 (m, 1H), 7.82(d, J=8 Hz, 2H), 7.41 (dd, J=10, 2 Hz, 1H), 7.32 (d, J=9 Hz, 2H),7.23-7.21 (m, 1H), 6.83 (s, 1H), 3.24 (s, 3H).

[1149] Anal. Calcd. for C₂₀H₁₃F₄N₃O₃S: C, 53.22; H, 2.90; N, 9.31.Found: C, 53.17; H, 2.99; N, 9.35.

Example 95

[1150]4-{4-[1-14-(Methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole

[1151] The title compound was prepared according to the procedure ofExample 94 using (4-methylsulfonylphenyl)hydrazine hydrochloride insteadof (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1152] mp: 175-177° C.

[1153]¹H-NMR (CDCl₃) δ: 8.01 (d, J=1 Hz, 1H), 7.97-7.94 (m, 3H), 7.78(d, J=9 Hz, 2H), 7.57 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H), 6.83 (s,1H), 3.07 (s, 3H).

[1154] Anal. Calcd. for C₂₀H₁₄F₃N₃O₃S: C, 55.43; H, 3.26; N, 9.70.Found: C, 55.11; H, 3.47; N, 9.41.

Example 96

[1155]2-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole

[1156] 4-Bromo-N-(2,2-diethoxyethyl)benzamide (Step 1)

[1157] To a stirred solution of aminoacetaldehyde diethyl acetal (6.66g, 50.0 mmol) in CH₂Cl₂ (100 ml) was added triethylamine (5.06 g, 50.0mmol), 4-bromobenzoyl chloride (10.97 g, 50.0 mmol), and the mixture wasstirred for 6 hours. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in ethyl acetate. The solution was washed with0.5N HCl aqueous solution, water, saturated NaHCO₃ aqueous solution,brine, dried over MgSO₄, and concentrated in vacuo. The residue wasrecystallized with ethyl acetate-hexane to give title compound (10.45 g,66% yield). ¹H-NMR (CDCl₃) δ: 7.65 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz,2H), 6.35 (s, 1H), 4.61 (t, J=5 Hz, 1H), 3.81-3.69 (m, 2H), 3.64-3.53(m, 4H), 1.24 (t, J=7 Hz, 6H).

[1158] 2-(4-Bromophenyl)-1,3-oxazole (Step 2)

[1159] 4-Bromo-N-(2,2-diethoxyethyl)benzamide was dissolved inconcentrated sulfuric acid at 0° C. To phosphorus pentoxide (5.2 g, 18.3mmol) was added the sulfuric acid solution, and the mixture was heatedat 180° c. for 30 minutes. The reaction mixture was cooled down to roomtemperature, and poured into ice. The whole was made basic by additionof NaHCO₃ and ammonia aqueous solution. The whole was extracted withethyl acetate. The organic layer was washed with brine, dried overMgSO₄, and concentrated in vacuo to give title compound (1.23 g, 70%yield).

[1160]¹H-NMR (DMSO-d₆) δ: 8.26 (s, 1H), 7.93 (d, J=9 Hz, 2H), 7.75 (d,J=9 Hz, 2H), 7.42 (s, 1H).

[1161] 1-[4-(1,3-Oxazol-2-yl)phenyl]-1-ethanone (Step 3)

[1162] The title compound was prepared according to the procedure ofExample 94 (step 2) using 2-(4-bromophenyl)-1,3-oxazole instead of4-(4-bromophenyl)-1,3-oxazole.

[1163]¹H-NMR (CDCl₃) δ: 8.15 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 7.77(d, J=1 Hz, 1H), 7.30 (d, J=1 Hz, 1H), 2.65 (s, 3H).

[1164] 4,4,4-Trifluoro-1-[4-(1,3-oxazol-2-yl)phenyl]-1,3-butanedione(Step 4)

[1165] The title compound was prepared according to the procedure ofExample 94 (step 3) using 1-[4-(1,3-oxazol-2-yl)phenyl]-1-ethanoneinstead of 1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound wasused for next reaction without purification.

[1166]2-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole(Step 5)

[1167] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-(1,3-oxazol-2-yl)phenyl]-1,3-butanedione instead of4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1168] mp: 140-142° C.

[1169]¹H-NMR (CDCl₃) δ: 8.11 (d, J=8 Hz, 2H), 7.93 (dd, J=8, 8 Hz, 1H),7.77 (d, J=1 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 7.38 (d, J=9 Hz, 2H), 7.29(d, J=1 Hz, 1H), 7.23 (dd, J=9, 2 Hz, 1H), 6.86 (s, 1H), 3.24 (s, 3H).

[1170] Anal. Calcd. for C₂₀H₁₃F₄N₃O₃S: C, 53.22; H, 2.90; N, 9.31.Found: C, 53.02; H, 3.01; N, 9.27.

Example 97

[1171]2-{4-1-[4-(Methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole

[1172] The title compound was prepared according to the procedure ofExample 96 using (4-methylsulfonylphenyl)hydrazine hydrochloride insteadof (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1173] mp: 190-192° C.

[1174]¹H-NMR (CDCl₃) δ: 8.07 (d, J=8 Hz, 2H), 7.96 (d, J=9 Hz. 2H), 7.76(s, 1H), 7.56 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H), 7.28-7.26 (m, 1H),6.83 (s, 1H), 3.07 (s, 3H).

[1175] Anal. Calcd. for C₂₀H₁₄F₃N₃O₃S {fraction (1/10)}Diisopropylether+½H₂O: C, 54.66; H, 3.65; N, 9.28. Found: C, 54.52; H, 3.58; N,8.98.

Example 98

[1176]4-[5-[4-(1,3-Oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1177] The title compound was prepared according to the procedure ofExample 96 using (4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1178] mp: 215-217° C.

[1179]¹H-NMR (DMSO-d₆) δ: 8.26 (s, 1H), 8.01 (d, J=8 Hz, 2H), 7.90 (d,J=8 Hz, 2H), 7.59 (d, J=9 Hz, 2H), 7.51-7.48 (m, 4H), 7.42 (s, 1H), 7.36(s, 1H).

[1180] Anal. Calcd. for C₁₉H₁₃F₃N₄O₃S 1.5H₂O: C, 49.46; H, 3.50; N.12.14. Found: C, 49.65; H, 3.44; N, 11.76.

Example 99

[1181]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1182] 4-(4-Bromophenyl)-1,3-thiazole (Step 1)

[1183] To a stirred solution of phosphorus pentasulfide (24.5 g, 55mmol) in dioxane (250 ml) was added formamide (28.4 g, 630 mmol), andthe mixture was heated at reflux temperature for 2 hours. The reactionmixture was cooled down to room temperature, and the solution wasdecanted away from solids. To a stirred solution of2,4′-dibromoacetophenone (15 g, 54 mmol) in dioxane (100 ml) was addedthe thioformamide solution, and the mixture was heated at refluxtemperature for 6 hours. The reaction mixture was cooled down to roomtemperature, and made basic by addition of 2N NaOH aqueous solution. Thewhole was extracted with diethyl ether. The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography eluting with CH₂Cl₂ to give titlecompound (12.3 g, 95% yield).

[1184]¹H-NMR (CDCl₃) δ: 8.87 (d, J=2 Hz, 1H), 7.80 (d, J=8 Hz, 2H), 7.56(d, J=8 Hz, 2H), 7.53 (d, J=2 Hz, 1H).

[1185] 1-[4-(1,3-Thiazol-4-yl)phenyl]-1-ethanone (Step 2)

[1186] The title compound was prepared according to the procedure ofExample 94 (step 2) using 4-(4-bromophenyl)-1,3-thiazole instead of4-(4-bromophenyl)-1,3-oxazole.

[1187]¹H-NMR (CDCl₃) δ: 8.92-8.90 (m, 1H), 8.04-8.02 (m, 4H), 7.69 (d,J=2 Hz, 1H), 2.64 (s, 3H).

[1188] 4,4,4-Trifluoro-]-[4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 3)

[1189] The title compound was prepared according to the procedure ofExample 94 (step 3) using 1-[4-(1,3-thiazol-4-yl)phenyl]-1-ethanoneinstead of 1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound wasused for next reaction without purification.

[1190]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole(Step 4)

[1191] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-(13-thiazol-4-yl)phenyl]-1,3-butanedione instead of4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1192] mp: 125-127° C.

[1193]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 8.01 (d, J=8 Hz, 2H),7.95-7.89 (m, 1H), 7.65 (d, J=2 Hz, 1H), 7.42 (dd, J=10, 2 Hz, 1H), 7.33(d, J=8 Hz, 2H), 7.27-7.22 (m, 1H), 6.84 (s, 1H), 3.23 (s, 3H).

[1194] Anal. Calcd. for C₂₀H₁₃F₄N₃O₂S₂ ¼ Hexane: C, 52.81; H, 3.40; N,8.59. Found: C, 52.98; H, 3.06; N, 8.91.

Example 100

[1195]4-[5-[4-(1,3-Thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1196] The title compound was prepared according to the procedure ofExample 99 using (4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1197] mp: 188-190° C.

[1198]¹H-NMR (DMSO-d₆) δ: 9.21 (d, J=2 Hz, 1H), 8.28 (d, J=2 Hz, 1H),8.04 (d, J=8 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 7.52(s, 2H), 7.41 (d, J=8 Hz, 2H), 7.31 (s, 1H).

[1199] Anal. Calcd. for C₁₉H₁₃F₃N₄O₂S₂ ½ Diisopropyl ether+½H₂O: C,51.76; H, 4.15; N, 10.97. Found: C, 51.92; H, 3.38; N, 10.83.

Example 101

[1200]4-{4-[1-[3-Methyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1201] The title compound was prepared according to the procedure ofExample 99 using (2-methyl-4-methylsulfonylphenyl)hydrazinehydrochloride instead of (2-fluoro-4-methylsulfonylphenyl)hydrazinehydrochloride.

[1202] mp: 147-149° C.

[1203]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H). 8.00-7.94 (m, 3H), 7.62(d, J=2 Hz, 1H), 7.53 (d, J=2 Hz, 1H), 7.31 (d, J=9 Hz, 2H), 7.21 (dd,J=9, 2 Hz, 1H), 6.83 (s, 1H), 3.09 (s, 3H), 2.70 (s, 3H).

[1204] Anal. Calcd. for C₂₁H₁₆F₃N₃O₂S₂: C, 54.42: H, 3.48; N, 9.07.Found: C, 54.38; H, 3.66; N, 8.98.

Example 102

[1205]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-2-methyl-1,3-thiazole

[1206] 4-(4-Bromophenyl)-2-methyl-1,3-thiazole (Step 1)

[1207] To a stirred solution of 2,4′-dibromoacetophenone (5 g, 18 mmol)in dioxane (180 ml) was added thioacetamide (6.76 g, 90 mmol), and themixture was heated at reflux temperature for 8 hours. The reactionmixture was cooled down to room temperature, and made basic by additionof 2N NaOH aqueous solution. The whole was extracted with diethyl ether.The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with ethyl acetate-hexane (1:5) to give title compound (4.73 g,99% yield).

[1208]¹H-NMR (CDCl₃) δ: 7.74 (d, J=8 Hz, 2H), 7.52 (d, J=8 Hz, 2H), 7.30(s, 3H), 2.76 (s, 3H).

[1209] 1-[4-(2-Methyl-1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 2)

[1210] The title compound was prepared according to the procedure ofExample 94 (step 2) using 4-(4-bromophenyl)-2-methyl-1,3-thiazoleinstead of 4-(4-bromophenyl)-1,3-oxazole.

[1211]¹H-NMR (CDCl₃) δ: 8.03-7.95 (m, 4H), 7.46 (s, 1H), 2.79 (s, 3H),2.63 (s, 3H).

[1212]4,4,4-Trifluoro-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 3)

[1213] The title compound was prepared according to the procedure ofExample 94 (step 3) using1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-1-ethanone instead of1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound was used for nextreaction without purification.

[1214]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-2-methyl-1,3-thiazole(Step 4)

[1215] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1216] mp: 139-141° C.

[1217]¹H-NMR (CDCl₃) δ: 7.95-7.88 (m, 3H), 7.43-7.39 (m, 2H), 7.32-7.23(m, 3H), 6.82 (s, 1H), 3.23 (s, 3H), 2.79 (s, 3H).

[1218] Anal. Calcd. for C₂₁H₁₅F₄N₃O₂S₂: C, 52.39; H, 3.14; N, 8.73.Found: C, 51.99; H, 3.33; N, 8.63.

Example 103

[1219]2-Fluoro-4-[5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1220] The title compound was prepared according to the procedure ofExample 99 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1221] mp: 168-170° C.

[1222]¹H-NMR (CDCl₃) δ: 8.88-8.87 (m, 1H), 7.94 (dd, J=9, 2 Hz, 2H),7.82-7.75 (m, 1H), 7.63-7.62 (m, 1H), 7.35-7.29 (m, 3H), 7.13 (d, J=9Hz, 1H), 6.81 (s, 1H), 5.75 (s, 2H). Anal. Calcd. for C₁₉H₁₂F₄N₄O₂S₂: C,48.72; H, 2.58; N, 11.96. Found: C, 48.59; H, 2.85; N, 11.75.

Example 104

[1223]4-{4-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-5-methyl-1-3-thiazole

[1224] 4-(4-Bromophenyl)-5-methyl-1,3-thiazole (Step 1)

[1225] The title compound was prepared according to the procedure ofExample 99 (step 1) using 2,4′-dibromopropiophenone instead of2,4′-dibromoacetophenone.

[1226]¹H-NMR (CDCl₃) δ: 8.65 (s, 1H), 7.60-7.53 (m, 4H), 2.59 (s, 3H).

[1227] 1-[4-(5-Methyl-1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 2)

[1228] The title compound was prepared according to the procedure ofExample 94 (step 2) using 4-(4-bromophenyl)-5-methyl-1,3-thiazoleinstead of 4-(4-bromophenyl)-1,3-oxazole.

[1229]¹H-NMR (CDCl₃) δ: 8.68 (s, 1H), 8.05 (d, J=9 Hz, 2H), 7.80 (d, J=9Hz, 2H), 2.65 (s, 3H), 2.64 (s, 3H).

[1230]4,4,4-Trifluoro-1-[4-(5-methyl-1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 3)

[1231] The title compound was prepared according to the procedure ofExample 94 (step 3) using1-[4-(5-methyl-1,3-thiazol-4-yl)phenyl]-1-ethanone instead of1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound was used for nextreaction without purification.

[1232]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-5-methyl-1,3-thiazole(Step 4)

[1233] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-(5-methyl-1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1234] mp: 170-172° C.

[1235]¹H-NMR (CDCl₃) δ: 8.67 (s, 1H), 7.94-7.88 (m, 1H), 7.77 (d, J=8Hz, 2H), 7.44 (dd, J=10, 2 Hz, 1H), 7.37 (d, J=8 Hz, 2H), 7.27 (dd, J=9,2 Hz, 1H), 6.85 (s, 1H), 3.23 (s, 3H), 2.65 (s, 3H).

[1236] Anal. Calcd. for C₂₁H₁₅F₄N₃O₂S₂ ⅕ Hexane+⅕H₂O: C, 53.08; H, 3.65;N, 8.36. Found: C, 52.77; H, 3.48; N, 7.99.

Example 105

[1237]4-{4-1-13-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-fluorophenyl}-1-3-thiazole

[1238] 1-(2-Fluoro-4-hydroxyphenyl)-1-ethanone (Step 1)

[1239] To a stirred suspension of aluminum chloride (42 g, 312 mmol) in1,2-dichloroethane (100 ml) was added 3-fluorophenol (31 g, 276 mmol)dropwise at 0° C. After addition, acetyl chloride (24 g, 306 mmol) wasadded dropwise and then the mixture was heated at reflux temperature for16 hours. The mixture was cooled down to room temperature, and pouredinto ice. The whole was extracted with diethylether. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was recystallized with hexane to give title compound (3.57 g, 8%yield).

[1240]¹H-NMR (CDCl₃) δ: 7.88-7.82 (m, 1H), 6.74 (dd, J=9, 2 Hz, 1H),6.64 (dd, J=13, 2 Hz, 1H), 2.62 (d, J=5 Hz, 3H).

[1241] 2-Bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (Step 2)

[1242] To a stirred solution of 1-(2-fluoro-4-hydroxyphenyl)-1-ethanone(2.56 g, 16.6 mmol) in dioxane (4 ml) was added a solution of bromine(2.70 g, 16.9 mmol) in dioxane (15 ml) dropwise, and the mixture wasstirred for 3 hours. The volatile was evaporated in vacuo, and theresidue was used for next reaction without purification. (2.4 g, 62%yield).

[1243]¹H-NMR (CDCl₃) δ: 7.95-7.89 (m, 1H), 6.73 (dd, J=9, 2 Hz, 1H),6.63 (dd, J=13, 3 Hz, 1H), 5.96 (s, 1H), 4.48 (d, J=3 Hz, 2H).

[1244] 3-Fluoro-4-(1,3-thiazol-4-yl)phenol (Step 3)

[1245] To a stirred solution of phosphorus pentasulfide (4.0 g, 9.0mmol) in dioxane (40 ml) was added formamide (4.8 g, 106 mmol), and themixture was heated at reflux temperature for 2 hours. The reactionmixture was cooled down to room temperature, and the solution wasdecanted away from solids. To a stirred solution of2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (1.2 g, 5.15 mmol) indioxane (14 ml) was added the thioformamide solution, and the mixturewas heated at reflux temperature for 6 hours. The reaction mixture wascooled down to room temperature, and made basic by addition of 2N NaOHaqueous solution. The whole was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate-hexane (1:4) to give title compound (864 g, 86% yield).

[1246]¹H-NMR (DMSO-d₆) δ: 10.03 (s, 1H), 9.04 (d, J=2 Hz, 1H), 7.89-7.83(m, 1H), 7.67-7.64 (m, 1H), 6.64-6.53 (m, 2H).

[1247] 3-Fluoro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate(Step 4)

[1248] To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenol (864mg, 4.43 mmol) in CH₂Cl₂ (27 ml) was added 2,6-lutidine (570 mg, 5.32mmol), 4-dimethylaminopyridine (108 mg, 0.89 mmol),trifluoromethanesulfonic anhydride (1.5 g, 5.32 mmol) at −30° C., andthe mixture was stirred for 1 hour, and then allowed to warm up to roomtemperature for 2 hours. The reaction mixture was diluted with water andthe whole was extracted with CH₂Cl₂. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo, and the residue wasused for next reaction without further purification. (1.45 g, 99%yield).

[1249] 1-[3-Fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 5)

[1250] To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate (1.45 g, 4.43 mmol) in dioxane (42 ml) wasadded tributyl(1-ethoxyvinyl)tin (1.92 g, 5.32 mmol),tetrakis(triphenylphosphine)palladium (512 mg, 0.44 mmol), lithiumchloride (466 mg, 11.0 mmol), and the mixture was heated at refluxtemperature for 16 hours. The reaction mixture was cooled down to roomtemperature, and diluted with ethyl acetate. The whole was washed withsaturated potassium fluoride aqueous solution, and the precipitate wasremoved by filteration through celite. The resulting solution wasextracted with ethyl acetate. The organic layer was concentrated invacuo. To the residue was added THF (20 ml), 2N HCl aqueous solution (20ml), and the mixture was heated at reflux temperature for 8 hours. Thereaction mixture was cooled down to room temperature, made neutral byaddition of NaHCO₃, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:5) to give title compound (666 mg, 68% yield).

[1251]¹H-NMR (CDCl₃) δ: 8.90-8.89 (m, 1H), 8.41-8.35 (m, 1H), 7.99-7.97(m, 1H), 7.83 (dd, J=8, 2 Hz, 1H), 7.75 (dd, J=12, 2 Hz, 1H), 2.63 (s,3H).

[1252]4,4,4-Trifluoro-1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 6)

[1253] To a stirred solution of1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl-1-ethanone (666 mg, 3.01 mmol),ethyl trifluoroacetate (470 mg, 3.31 mmol) in t-butylmethylether (40 ml)was added sodium methoxide (28 wt. % solution in methanol; 0.8 ml, 3.6mmol) over 5 minutes, and the mixture was stirred for 20 hours. Themixture was made neutral by addition of 2N HCl aqueous solution, and thewhole was extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo. The residue wasused for next reaction without purification. (1.06 g, 99% yield).

[1254]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-fluorophenyl}-1,3-thiazole(Step 7)

[1255] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1256] mp: 156-158° C.

[1257]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.37-8.31 (m. 1H),7.97-7.91 (m, 2H), 7.43 (dd, J=10, 2 Hz, 1H), 7.26 (dd, J=9, 2 Hz, 1H),7.17-7.10 (m, 2H), 6.86 (s, 1H), 3.24 (s, 3H).

[1258] Anal. Calcd. for C₂₀H₁₂F₅N₃O₂S₂: C, 49.48; H, 2.49; N, 8.66.Found: C, 49.58; H, 2.63; N, 8.49.

Example 106

[1259]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-thiazole

[1260] 2-Bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone (Step 1)

[1261] The title compound was prepared according to the procedure ofExample 105 (step 2) using 1-(4-hydroxy-2-methylphenyl)-1-ethanoneinstead of 1-(2-fluoro-4-hydroxyphenyl)-1-ethanone.

[1262]¹H-NMR (CDCl₃) o: 7.71 (d, J=9 Hz, 1H), 6.76-6.71 (m, 2H), 5.71(s, 1H), 4.40 (s, 2H), 2.55 (s, 3H).

[1263] 3-Methyl-4-(1,3-thiazol-4-yl)phenol (Step 2)

[1264] The title compound was prepared according to the procedure ofExample 105 (step 3) using2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone instead of2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone.

[1265]¹H-NMR (DMSO-d₆) δ: 9.46 (s, 1H), 9.10 (d, J=2 Hz, 1H), 7.59 (d,J=2 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 6.67-6.61 (m, 2H), 2.30 (s, 3H).

[1266] 3-Methyl-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate(Step 3)

[1267] The title compound was prepared according to the procedure ofExample 105 (step 4) using 3-methyl-4-(1,3-thiazol-4-yl)phenol insteadof 3-fluoro-4-(1,3-thiazol-4-yl)phenol. The compound was used for nextreaction without purification.

[1268] 1-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 4)

[1269] The title compound was prepared according to the procedure ofExample 105 (step 5) using 3-methyl-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate instead of 3-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate.

[1270]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.89-7.84 (m, 2H), 7.74(d, J=8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H).

[1271]4,4,4-Trifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 5)

[1272] The title compound was prepared according to the procedure ofExample 105 (step 6) using1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone instead of1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone.

[1273]¹H-NMR (CDCl₃) δ: 8.93 (d, J=2 Hz, 1H), 7.88-7.78 (m, 3H), 7.49(d, J=2 Hz, 1H), 6.61 (s, 1H), 2.56 (s, 3H).

[1274]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-thiazole(Step 6)

[1275] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1276] mp: 112-114° C.

[1277]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.95-7.90 (m, 1H), 7.65(d, J=8 Hz, 1H), 7.49-7.44 (m, 2H), 7.28-7.24 (m, 2H), 7.09 (dd, J=8, 2Hz, 1H), 6.81 (s, 1H), 3.24 (s, 3H), 2.48 (s, 3H).

[1278] Anal. Calcd. for C₂₁H₁₅F₄N₃O₂S₂: C, 52.39; H, 3.14; N, 8.73.Found: C, 52.65; H, 3.47; N, 8.42.

Example 107

[1279]4{-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-thiazole

[1280] 3-Bromophenyl acetate (Step 1)

[1281] To a stirred solution of 3-bromophenol (25 g, 145 mmol) in aceticanhydride (14 ml) was added a few drop of sulfuric acid, and the mixturewas stirred for 2 hours. The mixture was poured into a solution ofNaHCO₃ (1.3 g, 15.5 mmol) in water (160 ml). The whole was extractedwith diethylether. The organic layer was washed with saturated NaHCO₃aqueous solution, brine, dried over MgSO₄, and concentrated in vacuo.The residue was used for next reaction without purification. (31 g, 99%yield). ¹H-NMR (CDCl₃) δ: 7.39-7.35 (m, 1H), ?0.29-7.22 (m, 2H),7.07-7.02 (m, 1H), 2.30 (s, 3H).

[1282] 1-(4-Bromo-2-hydroxyphenyl)-1-ethanone (Step 2)

[1283] A mixture of 3-bromophenyl acetate (31 g, 145 mmol), aluminumchloride (34 g, 256 mmol) was heated at 160° c. for 2 hours. The mixturewas cooled down to room temperature, and poured into ice. The whole wasextracted with CH₂Cl₂. The organic layer was washed with brine, driedover MgSO₄, and concentrated in vacuo. The residue was used for nextreaction without further purification. (31 g, 99% yield). ¹H-NMR (CDCl₃)δ: 12.34 (s, 1H), 7.58 (d, J=9 Hz, 1H), 7.18 (d, J=2 Hz, 1H), 7.04 (dd,J=9, 2 Hz, 1H), 2.61 (s, 3H).

[1284] 1-(4-Bromo-2-methoxyphenyl)-1-ethanone (Step 3)

[1285] To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)-1-ethanone(28.8 g, 134 mmol), potassium carbonate (48.6 g, 352 mmol) in DMF (63ml) was added methyl iodide (25 g, 0.176 mmol), and the mixture wasstirred for 20 hours. The mixture was poured into water. The whole wasextracted with diethylether. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was used fornext reaction without purification. (31.5 g, 99% yield).

[1286]¹H-NMR (CDCl₃) δ: 7.62 (d, J=8 Hz. 1H). 7.17-7.12 (m, 2H), 3.92(s, 3H), 2.59 (s, 3H).

[1287] 2-Bromo-1-(4-bromo-2-methoxyphenyl)-1-ethanone (Step 4)

[1288] To a stirred solution of 1-(4-bromo-2-methoxyphenyl)-1-ethanone(31.5 g, 138 mmol) in dioxane (32 ml) was added a solution of bromine(21.8 g, 136 mmol) in dioxane (123 ml), and the mixture was stirred for3 hours. Then the volatile was evaporated in vacuo. The residue wasrecystallized with hexane-dichloromethane to give title compound (32.1g, 76% yield).

[1289]¹H-NMR (CDCl₃) δ: 7.70 (d, J=8 Hz, 1H), 7.19 (dd, J=8, 2 Hz, 1H),7.15 (d, J=2 Hz, 1H), 4.55 (s, 2H), 3.96 (s, 3H).

[1290] 4-(4-Bromo-2-methoxyphenyl)-1,3-thiazole (Step 5)

[1291] The title compound was prepared according to the procedure ofExample 99 (step 1) using 2-bromo-1-(4-bromo-2-methoxyphenyl)-1-ethanoneinstead of 2,4′-dibromoacetophenone.

[1292]¹H-NMR (CDCl₃) δ: 8.83 (d, J=2 Hz, 1H). 8.15 (d, J=8 Hz, 1H), 7.97(d, J=2 Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 7.14 (d, J=2 Hz, 1H), 3.96(s, 3H).

[1293] 1-[3-Methoxy-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 6)

[1294] The title compound was prepared according to the procedure ofExample 94 (step 2) using 4-(4-bromo-2-methoxyphenyl)-1,3-thiazoleinstead of 4-(4-bromophenyl)-1,3-oxazole.

[1295]¹H-NMR (CDCl₃) δ: 8.87 (d, J=2 Hz, 1H), 8.41 (d, J=9 Hz, 1H), 8.17(d, J=2 Hz, 1H), 7.67-7.64 (m, 2H), 4.04 (s, 3H), 2.65 (s, 3H).

[1296]4,4,4-Trifluoro-1-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 7)

[1297] The title compound was prepared according to the procedure ofExample 94 (step 3) using1-[2-methoxy-4-(1,3-thiazol-4-yl)phenyl)-1-ethanone instead of1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound was used for nextreaction without purification.

[1298]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-thiazole(Step 8)

[1299] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furl)phenyl]-1,3-butanedione.

[1300] mp: 155-157° C.

[1301]¹H-NMR (CDCl₃) δ: 8.86 (d, J=2 Hz, 1H), 8.34 (d, J=8 Hz, 1H), 8.09(d, J=2 Hz, 1H), 7.92 (dd, J=8, 7 Hz, 1H), 7.45 (dd, J=10, 2 Hz, 1H),7.30-7.26 (m, 1H), 6.94 (dd, J=8, 2 Hz, 1H), 6.90-6.85 (m, 2H), 3.88 (s,3H), 3.23 (s, 3H).

[1302] Anal. Calcd. for C₂₁H₁₅F₄N₃O₃S₂: C, 50.70; H, 3.04; N, 8.45.Found: C, 50.59; H, 3.18; N, 8.17.

Example 108

[1303]4-{[4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-oxazole

[1304] 4-(4-Bromo-2-methoxyphenyl)-1,3-oxazole (Step 1)

[1305] The title compound was prepared according to the procedure ofExample 94 (step 1) using 2-bromo-1-(4-bromo-2-methoxyphenyl)-1-ethanoneinstead of 2,4′-dibromoacetophenone.

[1306]¹H-NMR (CDCl₃) δ: 8.16 (d, J=1 Hz, 1H), 8.00 (d, J=8 Hz, 1H), 7.91(d, J=1 Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 7.10 (d, J=2 Hz, 1H), 3.96(s, 3H).

[1307]4,4,4-Trifluoro-1-[3-methoxy-4-(13-oxazol-4-yl)phenyl]-1,3-butanedione(Step 2)

[1308] The title compound was prepared according to the procedure ofExample 94 (step 2,3) using 4-(4-bromo-2-methoxyphenyl)-1,3-oxazoleinstead of 4-(4-bromophenyl)-1,3-oxazole. The compound was used for nextreaction without purification.

[1309]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-oxazole(Step 3)

[1310] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[3-methoxy-4-(1,3-oxazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furl)phenyl]-1,3-butanedione.

[1311] mp: 148-150° C.

[1312]¹H-NMR (CDCl₃) δ: 8.24 (d, J=1 Hz, 1H), 8.18 (d, J=8 Hz, 1H), 7.95(d, J=1 Hz, 1H), 7.92-7.89 (m, 1H). 7.43 (dd, J=10.2 Hz, 1H), 7.26 (dd,J=8, 2 Hz, 1H), 6.94 (dd, J=8, 2 Hz, 1H), 6.85-6.83 (m, 2H), 3.89 (s,3H), 3.23 (s, 3H).

[1313] Anal. Calcd. for C₂₁H₁₅F₄N₃O₄S: C, 52.39; H, 3.14: N, 8.73.Found: C, 52.33; H, 3.39; N, 8.46.

Example 109

[1314]4-{2-Chloro-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1315] 1-(4-Bromo-2-chlorophenyl)-1-ethanone (Step 1)

[1316] To a stirred solution of methylmagnesium iodide (0.82 M solutionin diethylether; 113 ml, 92.4 mmol) was added a solution of4-bromo-2-chlorobenzonitrile (10 g, 46.2 mmol) in diethylether (92 ml)dropwise, and the mixture was heated at reflux temperature for 16 hours.The mixture was cooled down to room temperature, added concentratedhydrochloric acid (50 ml), and the mixture was stirred for 5 hours. Thewhole was extracted with diethylether. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate-hexane(1:10) to give title compound (7.77 g, 72% yield).

[1317]¹H-NMR (CDCl₃) δ: 7.61 (dd, J=7, 1 Hz, 1H), 7.47-7.46 (m, 2H),2.64 (s, 3H).

[1318] 2-Bromo-1-(4-bromo-2-chlorophenyl)-1-ethanone (step 2)

[1319] To a stirred solution of 1-(4-bromo-2-chlorophenyl)-1-ethanone(11.58 g, 50 mmol) in dioxane (12 ml) was added a solution of bromine(8.12 g, 51 mmol) in dioxane (46 ml), and the mixture was stirred for 3hours. Then the volatile was evaporated in vacuo. The residue was usedfor next reaction without purification. (15.6 g, 99% yield).

[1320]¹H-NMR (CDCl₃) δ: 7.65 (d, J=2 Hz, 1H), 7.54-7.45 (m, 2H), 4.48(s, 2H).

[1321] 4-(4-Bromo-2-chlorophenyl)-1,3-thiazole (Step 3)

[1322] The title compound was prepared according to the procedure ofExample 99 (step 1) using 2-bromo-1-(4-bromo-2-chlorophenyl)-1-ethanoneinstead of 2,4′-dibromoacetophenone.

[1323]¹H-NMR (CDCl₃) δ: 8.87 (d, J=2 Hz, 1H), 7.92 (d, J=2 Hz, 1H), 7.88(d, J=8 Hz, 1H), 7.65 (d, J=2 Hz, 1H), 7.49 (dd, J=8, 2 Hz, 1H).

[1324] 1-[3-Chloro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 4)

[1325] The title compound was prepared according to the procedure ofExample 94 (step 2) using 4-(4-bromo-2-chlorophenyl)-1,3-thiazoleinstead of 4-(4-bromophenyl)-1,3-oxazole.

[1326]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 8.16 (d, J=8 Hz, 1H),8.09-8.07 (m, 2H), 7.91 (dd, J=8, 2 Hz, 1H), 2.64 (s, 3H).

[1327]4,4,4-Trifluoro-1-[3-chloro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 5)

[1328] The title compound was prepared according to the procedure ofExample 94 (step 3) using1-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone instead of1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound was used for nextreaction without purification.

[1329] 4-{2-Chloro-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole(Step 6)

[1330] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[3-chloro-4-(1,3-oxazol-4-yl)phenyl]1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furl)phenyl]-1,3-butanedione.

[1331] mp: 108-110° C.

[1332]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 8.05(d, J=2 Hz, 1H), 7.99-7.93 (m, 1H), 7.49 (d, J=2 Hz, 1H), 7.46 (dd,J=10, 2 Hz, 1H), 7.28-7.24 (m, 1H), 7.18 (dd, J=8, 2 Hz, 1H), 6.86 (s,1H), 3.24 (s, 3H).

[1333] Anal. Calcd. for C₂₀H₁₂ClF₄N₃O₂S₂ {fraction (1/10)} Hexane: C,48.46; H, 2.65; N, 8.23. Found: C, 48.28; H, 2.83; N, 8.10.

Example 110

[1334]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-oxazole

[1335] 3-Methyl-4-(1,3-oxazol-4-yl)phenol (Step 1)

[1336] A mixture of 2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone (18g, 78 mmol), ammonium formate (17 g, 273 mmol) in formic acid (100 ml)was heated at reflux temperature for 3 hours. The mixture was cooleddown to room temperature and made basic by addition of 50% NaOH aqueoussolution at 0° c. The whole was extracted with CH₂Cl₂. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:5) to give title compound (1.8 g, 13% yield).

[1337]¹H-NMR (DMSO-d₆) δ: 9.42 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.53(d, J=9 Hz, 1H), 6.62-6.58 (m, 2H).

[1338] 3-Methyl-4-(1,3-oxazol-4-yl)phenyl trifluoromethanesulfonate(Step 2)

[1339] The title compound was prepared according to the procedure ofExample 105 (step 4) using 3-methyl-4-(1,3-oxazol-4-yl)phenol instead of3-fluoro-4-(1,3-thiazol-4-yl)phenol.

[1340]4,4,4-Trifluoro-1-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-1,3-butanedione(Step 3)

[1341] The title compound was prepared according to the procedure ofExample 105 step 5,6) using 3-methyl-4-(1,3-oxazol-4-yl)phenyltrifluoromethanesulfonate instead of 3-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate. The compound was used for next reactionwithout purification.

[1342]4-{4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-oxazole(Step 4)

[1343] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-]-[[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furl)phenyl]-1,3-butanedione.

[1344] mp: 141-143° C.

[1345]¹H-NMR (CDCl₃) δ: 7.99 (d, J=1 Hz, 1H), 7.94-7.88 (m, 3H), 7.44(dd, J=10, 2 Hz, 1H), 7.26-7.22 (m, 2H), 7.12 (dd, J=8, 2 Hz, 1H), 6.80(s, 1H), 3.23 (s, 3H), 2.48 (s, 3H).

[1346] Anal. Calcd. for C₂₁H₁₅F₄N₃O₃S: C, 54.19; H, 3.25; N, 9.03.Found: C, 54.01; H, 3.21; N, 8.80.

Example 111

[1347]4-{2-Methoxy-4-[1-[4-(methylsulfonyl)phenyl]3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole

[1348] The title compound was prepared according to the procedure ofExample 108 using (4-methylsulfonylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1349] mp: 171-173° C.

[1350]¹H-NMR (CDCl₃) δ: 8.22 (d, J=1 Hz, 1H), 8.14 (d, J=8 Hz, 1H),7.97-7.94 (m, 3H), 7.59 (d, J=8 Hz, 2H), 6.94 (dd, J=8, 2 Hz, 1H), 6.85(s, 1H), 6.80 (d, J=2 Hz, 1H), 3.82 (s, 3H), 3.07 (s, 3H).

[1351] Anal. Calcd. for C₂₁H₁₆F₃N₃O₄S: C, 54.43; H, 3.48; N, 9.07.Found: C, 54.35; H, 3.50; N, 8.96.

Example 112

[1352]4-{2-Methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole

[1353] The title compound was prepared according to the procedure ofExample 110 using (4-methylsulfonylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1354] mp: 148-150° C.

[1355]¹H-NMR (CDCl₃) δ: 7.99-7.85 (m, 5H), 7.57 (d, J=8 Hz, 2H), 7.21(s, 1H), 7.09 (d, J=8 Hz, 1H), 6.81 (s, 1H), 3.06 (s, 3H), 2.45 (s, 3H).

[1356] Anal. Calcd. for C₂₁H₁₆F₃N₃O₃S: C, 56.37; H, 3.60; N, 9.39.Found: C, 56.46; H, 3.80; N, 9.17.

Example 113

[1357]2-Fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1358] The title compound was prepared according to the procedure ofExample 106 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1359] mp: 125-127° C.

[1360]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 7.89-7.83 (m, 1H), 7.64(d, J=8 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.26 (s,1H), 7.19 (dd, J=8, 2 Hz, 1H), 7.07 (dd, J=8, 2 Hz, 1H), 6.80 (s, 1H),5.26 (s, 2H), 2.47 (s, 3H).

[1361] Anal. Calcd. for C₂₀H₁₄F₄N₄O₂S₂ ½H₂O: C, 48.88; H, 3.08; N,11.40. Found: C, 48.61; H, 3.06; N, 11.26.

Example 114

[1362]2-Fluoro-4-[5-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1363] The title compound was prepared according to the procedure ofExample 105 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1364] mp: 196-198° C.

[1365]¹H-NMR (DMSO-d₆) δ: 9.14 (d, J=2 Hz, 1H), 8.09-8.03 (m, 2H),7.80-7.71 (m, 0.3H), 7.51 (dd, J=11, 2 Hz, 1H), 7.33 (dd, J=12, 2 Hz,1H), 7.28 (s, 1H), 7.27 (dd, J=8, 2 Hz, 1H), 7.13 (dd, J=8, 2 Hz, 1H).

[1366] Anal. Calcd. for C₁₉H₁₁F₅N₄O₂S₂: C, 46.91; H, 2.28; N, 11.52.Found: C, 46.91; H, 2.32; N, 11.33.

Example 115

[1367]4-{4-1-[3-Hydroxymethyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1368] The title compound was prepared according to the procedure ofExample 99 using (2-hydroxymethyl-4-methylsulfonylphenyl)hydrazinehydrochloride instead of (2-fluoro-4-methylsulfonylphenyl)hydrazinehydrochloride.

[1369] mp: 203-205° C.

[1370]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.00-7.95 (m, 3H), 7.79(d, J=2 Hz, 1H), 7.62 (d, J=2 Hz, 1H), 7.37-7.31 (m, 3H), 6.84 (s, 1H),4.95 (s, 2H), 3.17 (s, 3H).

[1371] Anal. Calcd. for C₂₁H₁₆F₃N₃O₂S₂ {fraction (1/20)}H₂O: C, 52.50;H, 3.38; N, 8.75. Found: C, 52.88; H, 3.77; N, 8.47.

Example 116

[1372]4-[5-[3-Methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1373] The title compound was prepared according to the procedure ofExample 110 using (4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1374] mp: 112-114° C.

[1375]¹H-NMR (CDCl₃) δ: 7.98 (d, J=1 Hz, 1H), 7.92 (d, J=9 Hz. 2H), 7.88(d, J=1 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.51 (d, J=9 Hz, 2H), 7.22 (s,1H), 7.08 (d, J=8 Hz, 1H), 6.80 (s, 1H), 4.95 (s, 2H), 2.45 (s, 3H).

[1376] Anal. Calcd. for C₂₀H₁₅F₃N₄O₃S ½H₂O: C, 52.52; H, 3.53; N, 12.25.Found: C, 52.20; H, 3.72; N, 11.99.

Example 117

[1377]4-5-[3-Methoxy-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1]H-pyrazol-1-yl]benzenesulfonamide

[1378] The title compound was prepared according to the procedure ofExample 108 using (4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1379] mp: 143-145° C.

[1380]¹H-NMR (CDCl₃) δ: 8.22 (s, 1H), 8.12 (d, J=8 Hz, 1H), 7.93-7.90(m, 3H), 7.52 (d, J=9 Hz, 2H), 6.91 (d, J=8 Hz, 1H), 6.84 (s, 1H), 6.80(s, 1H), 5.01 (s, 2H), 3.82 (s, 3H). Anal. Calcd. for C₂₀H₁₅F₃N₄O₄S{fraction (1/10)} Hexane: C, 52.31; H, 3.49; N, 11.84. Found: C, 52.28;H, 3.80; N, 11.51.

Example 118

[1381]4-[5-[4-(1,3-Oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1382] The title compound was prepared according to the procedure ofExample 94 using (4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1383] mp: 170-172° C.

[1384]¹H-NMR (CDCl₃) δ: 7.98 (d, J=11 Hz, 2H), 7.90 (d, J=9 Hz, 2H),7.75 (d, J=8 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 6.82(s, 1H), 5.15 (s, 2H).

[1385] Anal. Calcd. for C₁₉H₁₃F₃N₄O₃S ⅕ Hexane: C, 52.10; H, 3.08; N,12.79. Found: C, 51.88; H, 3.27; N, 12.48.

Example 119

[1386]4-{2-Chloro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1387] The title compound was prepared according to the procedure ofExample 109 using (4-methylsulfonylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1388] mp: 128-130° C.

[1389]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.05-7.98 (m. 4H), 7.59(d, J=9 Hz, 2H), 7.46 (d, J=2 Hz, 1H), 7.15 (dd, J=8, 2 Hz, 1H), 6.87(s, 1H), 3.08 (s, 3H).

[1390] Anal. Calcd. for C₂₀H₁₃ClF₃N₃O₂S₂: C, 49.64; H, 2.71; N, 8.68.Found: C, 49.70; H, 2.92; N, 8.54.

Example 120

[1391]4-{2-Methoxy-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1392] The title compound was prepared according to the procedure ofExample 107 using (4-methylsulfonylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1393] mp: 164-166° C.

[1394]¹H-NMR (CDCl₃) δ: 8.85 (d, J=2 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.06(d, J=2 Hz, 1H), 7.96 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 6.94 (dd,J=8, 2 Hz, 1H), 6.86-6.83 (m, 2H), 3.82 (s, 3H), 3.06 (s, 3H).

[1395] Anal. Calcd. for C₂₁H₁₆F₃N₃O₃S₂: C, 52.60; H, 3.36; N, 8.76.Found: C, 52.61; H, 3.52; N, 8.72.

Example 121

[1396]2-Fluoro-4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1397] The title compound was prepared according to the procedure ofExample 94 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1398] mp: Not Detected.

[1399]¹H-NMR (CDCl₃) δ: 8.00 (d, J=13 Hz, 2H), 7.90-7.84 (m, 2H), 7.81(d, J=8 Hz, 1H), 7.37 (dd, J=11, 2 Hz, 2H), 7.31 (d, J=8 Hz, 1H), 7.19(d, J=9 Hz, 1H), 6.82 (s, 1H), 5.12 (s, 2H).

[1400] Anal. Calcd. for C₁₉H₁₂F₄N₄O₃S {fraction (1/10)} Hexane+1/2H₂O:C, 50.09; H, 3.09; N, 11.92. Found: C, 50.39; H, 3.17; N, 11.59.

Example 122

[1401]2-Fluoro-4-[5-[3-chloro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1402] The title compound was prepared according to the procedure ofExample 109 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1403] mp: 173-175° C.

[1404]¹H-NMR (DMSO-d₆) δ: 9.24 (d, J=2 Hz, 1H), 8.27 (d, J=2 Hz, 1H),7.95-7.85 (m, 4H), 7.71 (d, J=2 Hz, 1H), 7.65 (dd, J=11, 2 Hz, 1H), 7.44(s, 1H), 7.41 (dd, J=8, 2 Hz, 1H), 7.31 (dd, J=8, 2 Hz, 1H).

[1405] Anal. Calcd. for C₁₉H₁₁ClF₄N₄O₂S₂: C, 45.38; H, 2.20; N, 11.14.Found: C, 45.28; H, 2.38; N, 11.00.

Example 123

[1406]2-Fluoro-4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1407] The title compound was prepared according to the procedure ofExample 110 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1408] mp: Not Detected.

[1409]¹H-NMR (CDCl₃) δ: 8.00 (s, 1H), 7.91-7.83 (m, 3H), 7.40 (dd, J=11,2 Hz, 1H), 7.26-7.24 (m, 1H), 7.18 (d, J=9 Hz, 1H), 7.11 (d, J=9 Hz,1H), 6.80 (s, 1H), 5.13 (s, 2H), 2.48 (s, 3H).

[1410] Anal. Calcd. for C₂₀H₁₄F₄N₄O₃S ½H₂O: C, 50.53; H, 3.18; N, 11.78.Found: C, 50.72; H, 3.36; N, 11.48.

Example 124

[1411]4-{2-Fluoro-4-[1-14-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1412] The title compound was prepared according to the procedure ofExample 105 using (4-methylsulfonylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1413] mp: 176-178° C.

[1414]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.33-8.27 (m, 1H), 7.98(d, J=9 Hz, 2H), 7.92-7.91 (m, 1H), 7.59 (d, J=9 Hz, 2H), 7.14-7.06 (m,2H), 6.86. (s, 1H), 3.08 (s, 3H). Anal. Calcd. for C₂₀H₁₃F₄N₃O₂S₂: C,51.39; H, 2.80; N, 8.99. Found: C, 51.45; H, 2.95; N, 8.81.

Example 125

[1415]4-{2-Methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[1416] The title compound was prepared according to the procedure ofExample 106 using (4-methylsulfonylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1417] mp: 140-142° C.

[1418]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 7.96 (d, J=9 Hz, 2H),7.64-7.57 (m, 3H), 7.42 (d, J=2 Hz, 1H), 7.24 (d, J=1 Hz, 1H), 7.07 (dd,J=8, 2 Hz, 1H), 6.82 (s, 1H), 3.07 (s, 3H), 2.45 (s, 3H).

[1419] Anal. Calcd. for C₂₁H₁₆F₃N₃O₂S₂: C, 54.42; H, 3.48; N, 9.07.Found: C, 54.52; H, 3.66; N, 8.95.

Example 126

[1420] Ethyl1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate

[1421] Ethyl5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate(Step 1)

[1422] The subtitle compound was prepared according to the procedure ofExample 85 using methyl 4-(4-bromophenyl)-2,4-diketobutyrate (preparedaccording to the method of J. Med. Chem., 1997, 40, 1347) instead of4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione in step 1.

[1423]¹H-NMR (CDCl₃) δ: 7.92 (dd, J=8, 9 Hz. 1H), 7.56 (d, J=8 Hz, 2H),7.43 (dd, J=2, 10 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 2H),7.04 (s, 1H), 4.46 (q, J=7 Hz, 2H), 3.24 (s, 3H), 1.43 (t, J=7 Hz. 3H).

[1424] Ethyl1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate(Step 2)

[1425] The title compound was prepared according to the procedure ofExample 85 using ethyl5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylateinstead of 5-(4-bromophenyl)1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazoleand 2-furanboronic acid instead of 3-furanboronic acid in step 2.

[1426] mp: 172.0° C.

[1427]¹H-NMR (CDCl₃) δ: 7.90 (dd, J=8, 9 Hz, 1H), 7.70 (d, J=9 Hz, 2H),7.51 (d, J=1 Hz, 1H), 7.46 (dd, J=2, 11 Hz, 1H), 7.28-7.24 (m, 3H), 7.07(s, 1H), 6.74 (d, J=3 Hz, 1H), 6.51 (dd, J=2, 4 Hz, 1H), 4.47 (q. J=7Hz, 2H), 3.23 (s, 3H), 1.44 (t, J=7 Hz, 3H).

[1428] Anal. Calcd. for. C₂₃H₁₉FN₂O₅S: C, 60.78; H, 4.21; N, 6.16.Found: C, 60.39; H, 4.38; N, 6.04.

[1429] mS (EI): m/z 454 (M⁺)

Example 127

[1430]1-[3-Ethoxy-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicAcid

[1431] To a stirred solution of ethyl1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate(0.57 g, 1.25 mmol) in ethanol (15 mL) was added 2N—NaOH solution inwater (1.6 mL, 3.14 mmol), and the mixture was heated at refluxtemperature for 30 minutes. After cooling, 2N—HCl solution (4-mL) andwater (30 mL) were added to the mixture. The whole was extracted withethyl acetate (20 mL×3), the organic layer was washed with brine, driedover MgSO₄, and concentrated in vacuo. The resulting solid was washedwith methylene chloride to give the title compound (0.413 g, 73.0%,yield).

[1432] mp: 256.0-257.0° C.

[1433]¹H-NMR (DMSO-d₆) δ: 7.73-7.60 (m, 4H), 7.25 (d, J=7 Hz, 2H), 7.16(s, 1H), 7.03 (d, J=2 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J=4 Hz, 1H), 6.50(t, J=2 Hz, 1H), 3.99 (q, J=7 Hz, 2H), 3.17 (s, 3H), 1.15 (t, J=7 Hz,3H).

[1434] Anal. Calcd. for. C₂₃H₂₀N₂O₆S, 0.3H₂O: C, 60.33; H, 4.53; N,6.12. Found: C, 60.07; H, 4.59; N, 5.94.

[1435] mS (EI): m/z 452 (M⁺)

Example 128

[1436]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicAcid

[1437] The title compound was prepared according to the procedure ofExample 127 using THF instead of ethanol.

[1438] mp: 171.5-173.0° C.

[1439]¹H-NMR (CDCl₃) δ: 7.92 (dd, J=8, 8 Hz, 1H), 7.71 (d, J=8 Hz, 2H),7.51 (d, J=2 Hz, 1H), 7.46 (dd, J=2, 10 Hz, 1H), 7.29-7.25 (m, 3H), 7.12(s, 1H), 6.75 (d, J=3 Hz, 1H), 6.51 (dd, J=2, 4 Hz, 1H), 3.24 (s, 3H).

[1440] Anal. Calcd. for. C₂₁H₁₅FN₂O₅S, 0.05Hexane, 0.6H₂O: C, 57.85; H,3.82; N, 6.36. Found: C, 57.92; H, 4.08; N, 5.97.

[1441] mS (EI): m/z 426 (M⁺)

Example 129

[1442]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-hydroxymethyl-1H-pyrazole

[1443] To a solution of1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicacid (0.1 g, 0.235 mmol) in THF (2 mL) at 0° C. was added dropwise 1Mborane-THF complex (0.7 mL). The mixture was stirred at room temperaturefor 3 hours. The solution was added water (1 mL) and ethyl acetate (20mL), and the mixture was washed with 1N HCl, saturated NaHCO₃, andbrine, dried over MgSO₄, filtered, and concentrated in vacuo. The crudemixture was purified by flash chromatography eluting with hexane/ethylacetate (1/1) to give the title compound (0.051 g, 52.6% yield).

[1444]¹H-NMR (CDCl₃) δ: 7.86 (dd, J=8, 8 Hz, 1H), 7.69 (d, J=8 Hz, 2H),7.51 (d, J=2 Hz, 1H), 7.36 (dd, J=2, 10 Hz, 1H), 7.27 (d, J=8 Hz, 2H),7.20 (d, J=9 Hz, 1H), 6.73 (d, J=4 Hz, 1H), 6.57 (s, 1H), 6.51 (dd, J=2,3, Hz, 1H), 4.81 (s, 2H), 3.22 (s, 3H)

[1445] Anal. Calcd. for. C₂₁H₁₇FN₂O₄S, 0.1H₂O: C, 60.89; H, 4.19; N,6.76. Found: C, 60.69; H, 4.56; N, 6.52.

[1446] mS (EI): m/z 412 (M⁺)

Example 130

[1447]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(4-morpholinecarbonyl)-1H-pyrazole.

[1448] A solution of1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicacid (0.2 g, 0.469 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC, 0.108 g, 0.563 mmol), and morpholine (0.04 mL, 0.492mmol) in methylene chloride (10 mL) was stirred at room temperature for3.5 hours. The mixture was diluted with methylene chloride (20 ml) andwashed with saturated NaHCO₃, water, and brine, dried over MgSO₄,filtered, and concentrated in vacuo. The crude mixture was purified byflash chromatography eluting with methylene chloride 1 methanol (30/1).The resulting solid was recrystallized from methylene chloride-hexane togive the title compound to give the title compound (0.1 g, 43.1% yield).

[1449] mp: 221.0-222.0° C.

[1450]¹H-NMR (CDCl₃) δ: 7.90 (dd, J=8, 8 Hz, 1H), 7.71 (d, J=8 Hz, 2H),7.51 (d, J=2 Hz, 1H), 7.35 (dd, J=2, 11 Hz, 1H), 7.29-7.26 (m. 0.2H),7.22 (d, J=8 Hz, 1H), 6.97 (s, 1H), 6.75 (d, J=3 Hz, 1H), 6.51 (dd, J=2,4 Hz, 1H), 4.14 (brs, 2H), 3.83-3.76 (m, 6H), 3.24 (s, 3H).

[1451] Anal. Calcd. for. C₂₅H₂₂FN₃O₅S, 0.05H₂O: C, 60.49; H, 4.49; N,8.46. Found: C, 60.19; H, 4.63; N, 8.28.

[1452] mS (EI): m/z 495 (M⁺)

Example 131

[1453]N-Methyl-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide

[1454] The title compound was prepared according to the procedure ofExample 130 using 2M-methylamine in THF solution instead of morpholine.

[1455] mp: 196.0-198.0° C.

[1456]¹H-NMR (CDCl₃) δ: 7.91 (dd, J=8, 8 Hz, 1H), 7.70 (d, J=8 Hz, 2H),7.51 (d, J=2 Hz, 1H), 7.37 (dd, J=2, 10 Hz, 1H), 7.27 (d, J=8 Hz, 2H),7.22 (d, J=2 Hz, 1H), 7.08 (s, 1H), 6.97-6.90 (brm, 1H), 6.74 (d, J=4Hz, 1H), 6.51 (dd, J=2, 4 Hz, 1H), 3.24 (s, 3H), 3.04 (d, J=5 Hz, 3H).

[1457] Anal. Calcd. for. C₂₂H₁₈FN₃O₄S: C, 60.13; H, 4.13; N, 9.56.Found: C, 60.02; H, 4.50; N, 9.21.

[1458] mS (EI): m/z 439 (M⁺)

Example 132

[1459]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide

[1460] The title compound was prepared according to the procedure ofExample 130 using 0.5M-ammonia in 1,4-dioxane solution instead ofmorpholine.

[1461] mp: 239.0-240.0° C.

[1462]¹H-NMR (CDCl₃) δ: 7.92 (dd, J=8, 8 Hz, 1H), 7.71 (d, J=8 Hz, 2H),7.51 (d, J=2 Hz, 1H), 7.24 (dd, J=2, 10 Hz, 1H), 7.27 (d, J=8 Hz, 2H),7.24-7.23 (m, 1H), 7.10 (s, 1H), 6.83 (brs, 1H), 6.75 (d, J=3 Hz, 1H),6.51 (dd, J=2, 3 Hz, 1H), 5.54 (brs, 1H), 3.25 (s, 3H).

[1463] Anal. Calcd. for. C₂₁H₁₆FN₃O₄S, 0.2H₂O: C, 58.79; H, 3.85; N,9.79. Found: C, 58.42; H, 4.01; N, 9.41.

[1464] mS (EI): m/z 425 (M⁺)

Example 133

[1465]N,N-Dimethyl-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide

[1466] The title compound was prepared according to the procedure ofExample 130 using dimethylamine hydrochloride and triethylamine insteadof morpholine.

[1467] mp: 167.0-168.0° C.

[1468]¹H-NMR (CDCl₃) δ: 7.89 (dd, J=8, 8 Hz, 1H), 7.70 (d, J=9 Hz, 2H),7.51 (d, J=1 Hz, 1H), 7.37 (dd, J=2, 11 Hz, 1H), 7.30-7.26 (m, 2H),7.25-7.20 (m, 1H), 6.95 (s, 1H), 6.74 (d, J=3 Hz, 1H), 6.51 (dd, J=2, 3Hz, 1H), 3.43 (s, 3H), 3.23 (s, 3H), 3.13 (s, 3H).

[1469] Anal. Calcd. for. C₂₃H₂₀FN₃O₄S: C, 60.92; H, 4.45; N, 9.27.Found: C, 60.64; H, 4.66; N, 9.06.

[1470] mS (EI): m/z 453 (M⁺)

Example 134

[1471]N-Methoxy-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide

[1472] The title compound was prepared according to the procedure ofExample 130 using methoxylamine hydrochloride and triethylamine insteadof morpholine.

[1473] mp: 126.0-128.0° C.

[1474]¹H-NMR (CDCl₃) δ: 9.38 (s, 1H), 7.92 (dd, J=8, 8 Hz, 1H), 7.70 (d,J=8 Hz, 2H), 7.51 (d, J=2 Hz, 1H), 7.36 (dd, J=2, 10 Hz, 1H), 7.27-7.21(m, 3H), 7.12 (s, 1H), 6.75 (d, J=4 Hz, 1H), 6.51 (dd, J=2, 4 Hz, 1H),3.93 (s, 3H), 3.25 (s, 3H).

[1475] Anal. Calcd. for. C₂₂H₁₈FN₃O₅S, 0.7H₂O, 0.1Hexane: C, 56.77; H,4.34; N, 8.87. Found: C, 57.00; H, 4.41; N, 8.50.

[1476] mS (EI): m/z 455 (M⁺)

Example 135

[1477]5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[1478] 4-(Methylsulfonyl)-3-(trifluoromethyl)nitrobenzene (Step 1)

[1479] A mixture of 2-fluoro-5-nitrobenzotrifluoride (2.09 g. 10 mmol)and sodium methanesulfinate (1.32 g, 1.1 mmol) in DMSO (20 mL) washeated at 130° C. for 17.5 hours. After cooling down to roomtemperature, the mixture was poured into ice-water. The whole wasextracted with ethyl acetate (30 mL×2), the combined organic layerwashed with water, brine, dried over MgSO₄, and concentrated in vacuo.The residue was crystallized from hexane to give the subtitle compound(1.56 g, 57.8%, yield).

[1480]¹H-NMR (CDCl₃) δ: 8.75 (m, 1H), 8.61-8.58 (m, 2H), 3.26 (s, 3H).

[1481] 4-(Methylsulfonyl)-3-(trifluoromethyl)aniline (Step 2)

[1482] A mixture of 4-(methylsulfonyl)-3-(trifluoromethyl)nitrobenzene(1.55 g, 5.76 mmol), iron powder (1.61 g, 28.8 mmol), and ammoniumchloride (0.03.1 g, 0.58 mmol) in ethanol (30 mL), and water (8 mL) washeated at reflux temperature for 1 hour. After cooling, insolubles werefiltered off by Celite, and volatiles were removed by evaporation. Theresidue was redissolved in ethyl acetate (50 mL) and the whole washedwith water and brine. After dried over MgSO₄ and concentration in vacuo.The residue was washed with hexane to give the subtitle compound (1.05g, 76.2%, yield).

[1483]¹H-NMR (CDCl₃) δ: 8.01 (d, J=9 Hz, 1H), 7.05 (d, J=3 Hz, 1H), 6.82(dd, J=3, 9 Hz, 1H), 4.47 (brs, 2H), 3.13 (s, 3H).

[1484] 4-(Methylsulfonyl)-3-(trifluoromethylphenylhydrazinehydrochloride (Step 3)

[1485] To a stirred suspension of4-(methylsulfonyl)-3-(trifluoromethyl)aniline (1.04 g, 4.35 mmol) inconc. HCl (10 mL) was added dropwise a solution of sodium nitrate (0.315g, 4.57 mmol) in water (10 mL) at −20° C. After stirring for 30 minutes,the resulting suspension was added Tin(II) chloride dihydrate (4.92 g,21.8 mmol) in conc.HCl (10 mL) at −10° C. After stirring for 1 hour at−5° C., the mixture was stirred further 1 hour at room temperature. Thereaction mixture was made alkaline with aqueous NaOH at 0-5° C. Themixture was filtered through Celite, the filterate was extracted withTHF (30 mL×3), the combined organic layer washed with brine, dried overMgSO₄ and concentration in vacuo to give the subtitle compound (1 g).

[1486]¹H-NMR (CDCl₃) δ: 8.06 (d, J=9 Hz, 1H), 7.04-6.97 (m, 2H), 5.95(brs, 1H), 3.77 (brs, 2H), 3.13 (s, 3H).

[1487] The solid (1 g) was dissolved in 10% methanolic HCl (3 mL), andvolatiles were removed by evaporation. The residue was recrystallizedfrom methylene chloride-ether to give the subtitle compound (0.869 g,68.8% yield, via 2 steps).

[1488]5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole(Step 4)

[1489] The title compound was prepared according to the procedure ofExample 60 using 4-(methylsulfonyl)-3-(trifluoromethyl)phenylhydrazinehydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazinehydrochloride in step 2.

[1490] mp: 159-160° C.

[1491]¹H-NMR (CDCl₃) δ: 8.26 (d, J=9 Hz, 1H), 8.05 (d, J=2 Hz, 1H), 7.72(d, J=8 Hz, 2H), 7.63 (dd, J=2, 9 Hz, 1H), 7.52 (d, J=2 Hz, 1H), 7.26(d, J=8 Hz, 2H), 6.83 (s, 1H), 6.76 (d, J=4 Hz, 1H), 6.52 (dd, J=2, 4Hz, 1H), 3.20 (s, 3H).

[1492] Anal. Calcd. for. C₂₂H₁₄F₆N₂O₃S: C, 52.80; H. 2.82; N, 5.60.Found: C, 53.09; H, 3.06; N, 5.46.

[1493] mS (EI): m/z 500 (M⁺)

Example 136

[1494]5-[4-(2-Furyl)phenyl]-1-[3-methoxy-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[1495] 3-Methoxy-4-(methylsulfonyl)nitrobenzene (Step 1)

[1496] The subtitle compound was prepared according to the procedure ofExample 135 using 2-chloro-5-nitroanisole instead of2-fluoro-5-nitrobenzotrifluoride in step 1. ¹H-NMR (CDCl₃) δ: 8.19 (d,J=8 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 4.13 (s,3H), 3.26 (s, 3H).

[1497] 3-Methoxy-4-(methylsulfonyl)aniline (Step 2)

[1498] The subtitle compound was prepared according to the procedure ofExample 135 using 3-methoxy-4-(methylsulfonyl)nitrobenzene instead of4-(methylsulfonyl)-3-(trifluoromethyl)nitrobenzene in step 2.

[1499]¹H-NMR (CDCl₃) δ: 7.69 (d, J=8 Hz, 1H), 6.21-6.21 (m, 2H), 4.21(brs, 2H), 3.91 (s, 3H), 3.15 (s, 3H).

[1500] 3-Methoxy-4-(methylsulfonyl)phenylhydrazine hydrochloride (Step3)

[1501] The subtitle compound was prepared according to the procedure ofExample 135 using 3-methoxy-4-(methylsulfonyl)aniline instead of4-(methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1502]5-[4-(2-Furyl)phenyl]-1-[3-methoxy-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole(Step 4)

[1503] The title compound was prepared according to the procedure ofExample 60 using 3-methoxy-4-(methylsulfonyl)phenylhydrazinehydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazinehydrochloride in step 2.

[1504] mp: 138.9° C.

[1505]¹H-NMR (CDCl₃) δ: 7.92 (d, J=9 Hz. 1H), 7.69 (d. J=8 Hz, 2H), 7.51(s, 1H), 7.28-7.26 (m, 2H), 7.17 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.81 (s,1H), 6.73 (s, 1H), 6.51 (s, 1H), 3.90 (s, 3H). 3.21 (s, 3H).

[1506] Anal. Calcd. for. C₂₂H₁₇F₃N₂O₄S: C, 57.14. H, 3.71; N, 6.06.Found: C, 57.10; H, 3.88; N, 6.09.

[1507] mS (EI): m/z 462 (M⁺)

Example 137

[1508]2-Fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1509] 4-Acetamido-2-fluorobenzenesulfonamide (Step 1)

[1510] To a stirred chlorosulfonic acid (33 mL, 0.5 mol) was addeddropwise 3-fluoroacetanilide (15.3 g, 0.1 mol) at 0° C. The mixture washeated at 70° C. for 6 hours and cooled down to room temperature. Themixture was diluted with methylene chloride (50 mL) and poured intoice-water. The whole was extracted with methylene chloride (30 mL×2).The combined organic layer was added 25% ammonium hydroxide (20 mL) at0° C., and the mixture was stirred for 1 hour at room temperature. Thesuspension was filtered to give the subtitle compound (11.17 g, 48.1%yield, via 2 steps).

[1511]¹H-NMR (DMSO-d₆) δ: 10.47 (s, 1H), 7.77-7.68 (m, 2H), 7.54 (brs,2H), 7.38 (dd, J=2, 9 Hz, 1H), 2.10 (s, 3H).

[1512] 4-Amino-2-fluorobenzenesulfonamide (Step 2)

[1513] A mixture of 4-acetamido-2-fluorobenzenesulfonamide (11.15 g, 48mmol) and sodium hydroxide (11.5 g, 480 mmol) in water (80 mL) washeated at reflux temperature for 3 hours. The mixture was made neutralby addition of 2N—HCl solution, and resulting suspension was filtered togive the subtitle compound (5.8 g, 63.5% yield).

[1514]¹H-NMR (DMSO-d₆) δ: 7.41-7.34 (m, 1H), 7.14 (brs, 2H), 6.39 (brs,1H), 6.36-6.33 (m, 1H), 6.11 (brs, 2H).

[1515] 3-Fluoro-4-sulfamoylphenylhydrozine hydrochloride (Step 3)

[1516] The subtitle compound was prepared according to the procedure ofExample 135 using 4-amino-2-fluorobenzenesulfonamide instead of4-(methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1517]¹H-NMR (DMSO-d₆) o: 7.71 (brs, 1H), 7.42 (t, J=9 Hz, 1H), 7.15(brs, 2H), 6.61-6.49 (brs, 2H), 4.26 (brs, 2H).

[1518]2-Fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 4)

[1519] The title compound was prepared according to the procedure ofExample 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride instep 2.

[1520] mp: 151.0° C.

[1521]¹H-NMR (CDCl₃) δ: 7.86 (dd, J=8, 8 Hz, 1H), 7.71 (d, J=9 Hz, 2H),7.51 (dd, J=1, 1 Hz, 1H), 7.38 (dd, J=2, 11 Hz, 1H), 7.26 (d, J=9 Hz,2H), 7.21-7.16 (m, 1H), 6.80 (s, 1H), 6.75 (d, J=4 Hz, 1H), 6.51 (dd,J=2, 4 Hz, 1H), 5.12 (brs, 2H).

[1522] Anal. Calcd. for. C₂₀H₁₃F₄N₃O₃S: C, 53.22; H, 2.90; N, 9.31.Found: C, 53.38; H. 3.18; N, 8.93.

[1523] mS (EI): m/z 451 (M⁺)

Example 138

[1524]4-[5-[3-Chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-fluorobenzenesulfonamide

[1525] The title compound was prepared according to the procedure ofExample 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and4,4,4-trifluoro-1-[3-chloro-4-(2-furyl)phenyl]butane-1,3-dione insteadof 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.

[1526] mp: 171.8° C.

[1527]¹H-NMR (CDCl₃) δ: 7.92-7.86 (m, 2H), 7.55 (dd, J=1, 2 Hz. 1H),7.45-7.38 (m, 2H), 7.27-7.26 (m, 1H), 7.18 (dd, J=2, 8 Hz, 1H), 7.10(dd, J=2, 8 Hz, 1H), 6.83 (s, 1H), 6.57 (dd, J=2, 4 Hz, 1H), 5.13 (brs,2H).

[1528] Anal. Calcd. for. C₂₀H₁₂ClF₄N₃O₃S, 0.1Hexane: C, 49.84; H, 2.67;N, 8.55. Found: C, 49.95; H, 2.78; N, 8.30.

[1529] mS (EI): m/z 485 (M⁺)

Example 139

[1530]2-Fluoro-4-[5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1531] The title compound was prepared according to the procedure ofExample 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and4,4,4-trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione insteadof 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.

[1532] mp: 78-80° C.

[1533]¹H-NMR (CDCl₃) δ: 7.85 (dd, J=8, 8 Hz, 1H), 7.73 (d, J=8 Hz, 1H),7.54 (d, J=2, 1H), 7.40 (dd, J=2, 11 Hz, 1H), 7.19 (d, J=9 Hz, 2H), 7.05(d, J=8 Hz, 1H), 6.79 (s, 1H), 6.65 (d, J=4 Hz, 1H), 6.54 (dd, J=2, 4Hz, 1H), 5.14 (brs, 2H), 2.51 (s, 3H).

[1534] Anal. Calcd. for. C₂₁H₁₅F₄N₃O₃S: C, 54.19; H, 3.25; N, 9.03.Found: C, 54.24; H, 3.56; N, 8.87.

[1535] mS (EI): m/z 465 (M⁺)

Example 140

[1536]3-Chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1537] 3-Chloro-4-fluorobenzenesulfonamide (Step 1)

[1538] To a solution of 3-chloro-4-fluorobenzenesulfonyl chloride (2.29g, 10 mmol) in methylene chloride (30 mL) was added 25% ammoniumhydroxide (10 mL) at room temperature and the mixture was stirred for 1hour. The solvent was removed in vacuo. The residue was redissolved inethyl acetate (50 mL) and the whole washed with water and brine. Afterdried over MgSO₄ and concentration in vacuo. The resulting solid wasrecrystallized from ether-hexane to give the title compound (1.429 g,68.2% yield).

[1539]¹H-NMR (DMSO-d₆) δ: 8.00 (dd, J=2, 7 Hz, 1H), 7.83 (ddd, J=2, 7, 9Hz, 1H), 7.65 (t, J=9 Hz, 1H), 7.54 (brs, 2H).

[1540] 2-Chloro-4-sulfamoylphenylhydrazine hydrochloride (Step 2)

[1541] The title compound was prepared according to the procedure ofExample 61 using 3-chloro-4-fluorobenzenesulfonamide instead of4-chlorophenyl fluoromethyl sulfone in step 1.

[1542]¹H-NMR (CDCl₃) δ: 7.59 (s, 1H), 7.27-7.21 (m, 3H), 7.09 (brs, 2H),4.33 (brs, 2H).

[1543]3-Chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 3)

[1544] The title compound was prepared according to the procedure ofExample 60 using 2-chloro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride instep 2.

[1545] mp: 190.3° C.

[1546]¹H-NMR (CDCl₃) δ: 8.01 (d, J=2 Hz, 1H), 7.91 (dd, J=2, 8 Hz, 1H),7.66-7.59 (m, 3H), 7.47 (d, J=2 Hz, 1H), 7.18 (d, J=9 Hz, 2H), 6.84 (s,1H), 6.69 (d, J=4 Hz, 1H), 6.47 (dd, J=2, 4 Hz, 1H), 5.07 (brs, 2H).

[1547] Anal. Calcd. for. C₂₀H₁₃ClF₃N₃O₃S, 0.05Hexane: C, 51.54; H, 2.89;N, 8.93. Found: C, 51.19; H, 3.20; N, 8.57.

[1548] mS (EI): m/z 467 (M⁺)

Example 141

[1549]3-Fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1550] 3,4-Difluorobenzenesulfonamide (Step 1)

[1551] The subtitle compound was prepared according to the procedure ofExample 137 using 1,2-difluorobenzene instead of 3-fluoroacetanilide instep 1.

[1552]¹H-NMR (CDCl₃) δ: 7.80-7.71 (m, 2H). 7.39-7.27 (m, 1H), 5.06 (brs,2H).

[1553] 2-Fluoro-4-sulfamoylphenylhydrazine hydrochloride (Step 2)

[1554] The title compound was prepared according to the procedure ofExample 61 using 3,4-difluorobenzenesulfonamide instead of4-chlorophenyl fluoromethyl sulfone in step 1.

[1555]3-Fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 3)

[1556] The title compound was prepared according to the procedure ofExample 60 using 2-fluoro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride instep 2.

[1557] mp: 174.4° C.

[1558]¹H-NMR (CDCl₃) δ: 7.84 (m, 1H), 7.77-7.68 (m, 2H), 7.63 (dd, J=2,9 Hz, 2H), 7.49 (d, J=2 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 6.83 (s, 1H),6.71 (d, J=3 Hz, 1H), 6.49 (dd, J=2, 3 Hz, 1H), 4.94 (brs, 2H).

[1559] Anal. Calcd. for. C₂₀H₁₃F₄N₃O₃S, 0.3H₂O: C, 52.59; H, 3.00; N,9.20. Found: C, 52.85; H, 3.14; N, 8.83.

[1560] mS (EI): m/z 451 (M⁺)

Example 142

[1561]5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)-2-methylphenyl]-3-trifluoromethyl-1H-pyrazole

[1562] 2-Methyl-4-(methylsulfonyl)nitrobenzene (Step 1)

[1563] The subtitle compound was prepared according to the procedure ofExample 135 using 5-fluoro-2-nitrotoluene instead of2-fluoro-5-nitrobenzotrifluoride in step 1. ¹H-NMR (CDCl₃) δ: 8.09 (d,J=8 Hz, 1H), 7.98-7.92 (m, 2H), 3.12 (s, 3H), 2.68 (s,

[1564] 2-Methyl-4-(methylsulfonyl)aniline (Step 2)

[1565] The subtitle compound was prepared according to the procedure ofExample 135 using 2-methyl-4-(methylsulfonyl)nitrobenzene instead of4-(methylsulfonyl)-3-(trifluoromethyl)nitrobenzene in step 2.

[1566]¹H-NMR (CDCl₃) δ: 7.59 (s, 1H), 7.56 (d, J=2 Hz, 1H), 6.71 (dd,J=1, 7 Hz, 1H), 0.17 (brs, 2H), 3.00 (s, 3H), 2.20 (s, 3H).

[1567] 2-Methyl-4-(methylsulfonyl)phenylhydrazine hydrochloride (Step 3)

[1568] The subtitle compound was prepared according to the procedure ofExample 135 using 2-methyl-4-(methylsulfonyl)aniline instead of4-(methylsulfonyl)-3-trifluoromethyl)aniline in step 3.

[1569][5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)-2-methylphenyl]-3-trifluoromethyl-1H-pyrazole(Step 4)

[1570] The title compound was prepared according to the procedure ofExample 60 using 2-methyl-4-(methylsulfonyl)phenylhydrazinehydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazinehydrochloride in step 2.

[1571] mp: 205.0° C.

[1572]¹H-NMR (CDCl₃) δ: 7.89-7.83 (m, 2H), 7.60 (d, J=9 Hz, 2H),7.50-7.47 (m, 2H), 7.14 (d, J=9 Hz, 2H), 6.86 (s, 1H), 6.69 (d, J=3 Hz,1H), 6.48 (dd, J=2, 4 Hz, 1H), 3.07 (s, 3H), 2.12 (s, 3H).

[1573] Anal. Calcd. for. C₂₂H₁₇F₃N₂O₃S: C, 59.19; H, 3.84; N, 6.27.Found: C, 59.32; H, 4.13; N, 6.17.

[1574] mS (EI): m/z 446 (M⁺)

Example 143

[1575]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbenzenesulfonamide

[1576] 4-Acetamido-2-methylbenzenesulfonamide (Step 1)

[1577] The subtitle compound was prepared according to the procedure ofExample 137 using m-acetotoluidide instead of 3-fluoroacetanilide instep 1.

[1578]¹H-NMR (DMSO-d₆) δ: 10.2 (s, 1H), 7.78 (s, 1H). 7.74 (s, 1H), 7.56(m, 1H), 7.53 (s, 2H), 2.54 (s, 3H), 2.06 (s, 3H).

[1579] 4-Amino-2-methylbenzenesulfonamide (Step 2)

[1580] The subtitle compound was prepared according to the procedure ofExample 137 using 4-acetamido-2-methylbenzenesulfonamide instead of4-acetamido-2-fluorobenzenesulfonamide in step 2.

[1581]¹H-NMR (DMSO-d₆) δ: 7.48 (d, J=8 Hz, 1H), 6.88 (brs, 2H), 6.42 (s,1H), 6.38 (dd, J=2, 8 Hz, 1H), 5.68 (brs, 2H), 2.42 (s, 3H).

[1582] 3-Methyl-4-sulfamoylphenylhydrozine hydrochloride (Step 3)

[1583] The subtitle compound was prepared according to the procedure ofExample 135 using 4-amino-2-methylbenzenesulfonamide instead of4-(methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1584]¹H-NMR (DMSO-d₆) δ: 7.55 (d, J=9 Hz, 1H), 7.29 (brs, 1H), 6.90(brs, 2H), 6.62 (s, 1H), 6.59 (dd, J=3, 9 Hz, 1H), 4.10 (brs, 2H), 2.46(s, 3H).

[1585]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbenzenesulfonamide(Step 4)

[1586] The title compound was prepared according to the procedure ofExample 60 sing 3-methyl-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-methylsulfonyl)phenylhydrazine hydrochloride instep 2.

[1587] mp: 137.4° C.

[1588]¹H-NMR (CDCl₃) δ: 7.95 (d, J=9 Hz. 1H), 7.67 (d, J=8 Hz. 2H), 7.50(d, J=2 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.24 (d, J=8 Hz. 2H), 7.14 (dd,J=2, 9 Hz, 1H), 6.79 (s, 1H), 6.73 (d, J=4 Hz, 1H), 6.50 (dd, J=2, 3 Hz,1H), 4.91 (brs, 2H). 2.67 (s, 3H).

[1589] Anal. Calcd. for. C₂₁H₁₆F₃N₃O₃S: C, 56.37; H, 3.60; N, 9.39.Found: C, 56.6“0; H, 3.85; N, 9.04.

[1590] mS (EI): m/z 447 (M⁺)

Example 144

[1591]2-Chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1592] 4-Acetamido-2-chlorobenzenesulfonamide (Step 1)

[1593] The subtitle compound was prepared according to the procedure ofExample 137 using m-chloroacetanilide instead of 3-fluoroacetanilide instep 1.

[1594]¹H-NMR (DMSO-d₆) δ: 10.4 (s, 1H), 7.94 (d, J=2 Hz, 1H), 7.90 (d,J=9 Hz, 1H), 7.56 (dd, J=2, 9 Hz, 1H), 7.36 (brs, 2H), 2.10 (s, 3H).

[1595] 4-Amino-2-chlorolbenzenesulfonamide (Step 2)

[1596] The subtitle compound was prepared according to the procedure ofExample 137 using 4-acetamido-2-chlorobenzenesulfonamide instead of4-acetamido-2-fluorobenzenesulfonamide in step 2.

[1597]¹H-NMR (DMSO-d₆) δ: 7.58 (d, J=9 Hz, 1H), 7.09 (brs, 2H), 6.67 (d,J=2 Hz, 1H), 6.50 (dd, J=2, 9 Hz, 1H), 6.07 (brs, 2H).

[1598] 3-Chloro-4-sulfamoylphenylhydrozine hydrochloride (Step 3)

[1599] The subtitle compound was prepared according to the procedure ofExample 135 using 4-amino-2-chlorolbenzenesulfonamide instead of4-(methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1600]¹H-NMR (DMSO-d₆) δ: 7.67 (brs, 1H), 7.58 (d, J=9 Hz, 1H), 7.11(brs, 2H), 6.87 (d, J=2 Hz, 1H), 6.66 (dd, J=2, 9 Hz, 1H), 4.27 (brs,2H)).

[1601]2-Chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 4)

[1602] The title compound was prepared according to the procedure ofExample 60 using 3-chloro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazne hydrochloride instep 2.

[1603] mp: 192.6° C.

[1604]¹H-NMR (CDCl₃) δ: 8.03 (d, J=9 Hz, 1H), 7.73-7.68 (m, 3H), 7.51(s, 1H), 7.28-7.23 (m, 3H), 6.80 (s, 1H), 6.75 (d, J=3 Hz, 1H), 6.51(dd, J=2, 4 Hz, 1H), 5.19 (brs, 2H). Anal. Calcd. for. C₂₀H₁₃ClF₃N₃O₃S,0.1H₂O: C, 51.15; H, 2.83; N, 8.95. Found: C, 51.26; H, 3.12; N, 8.55.

[1605] mS (EI): m/z 467 (M⁺)

Example 145

[1606]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-methylbenzenesulfonamide

[1607] 4-Acetamido-3-methylbenzenesulfonamide (Step 1)

[1608] The subtitle compound was prepared according to the procedure ofExample 137 using o-acetotoluidide instead of 3-fluoroacetanilide instep 1.

[1609]¹H-NMR (DMSO-d₆) δ: 9.47 (s, 1H), 7.94 (brs, 1H), 7.72-7.36 (m,4H), 2.26 (s, 3H), 2.09 (s, 3H).

[1610] 4-Amino-3-methylbenzenesulfonamide (Step 2)

[1611] The subtitle compound was prepared according to the procedure ofExample 137 using 4-acetamido-3-methylbenzenesulfonamide instead of4-acetamido-2-fluorobenzenesulfonamide in step 2.

[1612] 2-Methyl-4-sulfamoylphenylhydrozine hydrochloride (Step 3)

[1613] The subtitle compound was prepared according to the procedure ofExample 135 using 4-amino-3-methylbenzenesulfonamide instead of4-(methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1614]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-methylbenzenesulfonamide(Step 4)

[1615] The title compound was prepared according to the procedure ofExample 60 using 2-methyl-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride instep 2.

[1616] mp: 87-89° C.

[1617]¹H-NMR (CDCl₃) δ: 7.86-7.80 (m, 2H), 7.59 (d, J=8 Hz, 2H), 7.47(s, 1H), 7.43 (d, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 2H), 6.85 (s, 1H), 6.68(d, J=3 Hz, 1H), 6.48 (m, 1H), 4.95 (brs, 2H), 2.08 (s, 3H).

[1618] Anal. Calcd. for. C₂₁H₁₆F₃N₃O₃S, 0.1H₂O: C, 56.15; H, 3.63; N,9.35. Found: C, 56.02; H, 3.91; N, 8.97.

[1619] mS (EI): m/z 447 (M⁺)

Example 146

[1620][5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)-2-methoxy]phenyl]-3-trifluoromethyl-1H-pyrazole

[1621] 2-Methoxy-4-(methylsulfonyl)nitrobenzene (Step 1)

[1622] The subtitle compound was prepared according to the procedure ofExample 135 using 5-chloro-2-nitroanisole instead of2-fluoro-5-nitrobenzotrifluoride in step 1.

[1623]¹H-NMR (CDCl₃) δ: 7.80 (d, J=8 Hz, 1H), 7.67 (d, J=1 Hz, 1H), 7.62(dd, J=2, 8 Hz, 1H), 4.06 (s, 3H), 3.11 (s, 3H).

[1624] 2-Methoxy-4-(methylsulfonyl)aniline (Step 2)

[1625] The subtitle compound was prepared according to the procedure ofExample 135 using 2-methoxy-4-(methylsulfonyl)nitrobenzene instead of4-(methylsulfonyl)-3-(trifluoromethyl)nitrobenzene in step 2.

[1626]¹H-NMR (CDCl₃) δ: 7.38 (dd, J=2, 8 Hz, 1H), 7.27 (s, 1H), 6.74 (d,J=8 Hz, 1H), 4.36 (brs, 2H), 3.92 (s, 3H), 3.02 (s, 3H).

[1627] 2-Methoxy-4-(methylsulfonyl)phenylhydrazine hydrochloride (Step3)

[1628] The subtitle compound was prepared according to the procedure ofExample 135 using 2-methoxy-4-(methylsulfonyl)aniline instead of4-(Methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1629]¹H-NMR (CDCl₃) δ: 7.51 (dd, J=2, 8 Hz, 1H), 7.23 (d, J=2 Hz, 1H),7.10 (d, J=8 Hz, 1H), 6.07 (brs, 1H), 3.90 (s, 3H), 3.63 (brs, 2H), 3.02(s, 3H).

[1630][5-[4-(2-Furyl)phenyl]1-[4-(methylsulfonyl)-2-methoxy]phenyl]-3-trifluoromethyl-1H-pyrazole(Step 4)

[1631] The title compound was prepared according to the procedure ofExample 60 using 2-methoxy-4-(methylsulfonyl)phenylhydrazinehydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazinehydrochloride in step 2.

[1632] mp: 200.2° C.

[1633]¹H-NMR (CDCl₃) δ: 7.76 (d, J=8 Hz, 1H), 7.67 (dd, J=2,8-Hz, 1H),7.60 (d, J=9 Hz, 2H), 7.48 (dd, J=1, 2 Hz, 1H), 7.42 (d, J=2 Hz, 1H),7.19 (d, J=9 Hz, 2H), 6.80 (s, 1H), 6.69 (d, J=4 Hz, 1H), 6.48 (dd, J=2,4 Hz, 1H), 3.52 (s, 3H), 3.08 (s, 3H).

[1634] Anal. Calcd. for. C₂₂H₁₇F₃N₂O₄S: C, 57.14; H, 3.71; N, 6.06.Found: C, 57.06; H, 3.68; N, 5.96.

[1635] mS (EI): m/z 462 (M⁺)

Example 147

[1636][5-[4-(2-Furyl)phenyl]-1-[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[1637] 4-(Methylsulfonyl)-2-(trifluoromethyl)nitrobenzene (Step 1)

[1638] The subtitle compound was prepared according to the procedure ofExample 135 using 5-fluoro-2-nitrobenzotrifluoride instead of2-fluoro-5-nitrobenzotrifluoride in step 1.

[1639]¹H-NMR (CDCl₃) δ: 8.41 (s, 1H), 8.34 (d, J=8 Hz, 1H), 8.06 (d, J=8Hz, 1H), 3.16 (s, 3H).

[1640] 4-(Methylsulfonyl)-2-(trifluoromethyl)aniline (Step 2)

[1641] The subtitle compound was prepared according to the procedure ofExample 135 using 4-(methylsulfonyl)-2-(trifluoromethyl)nitrobenzeneinstead of 4-methylsulfonyl)-3-(trifluoromethyl)nitrobenzene in step 2.

[1642]¹H-NMR (CDCl₃) δ: 8.01 (s, 1H), 7.82 (dd, J=2, 9 Hz, 1H), 6.83 (d,J=9 Hz, 1H), 4.76 (brs, 2H), 3.03 (s, 3H).

[1643] 4-(Methylsulfonyl)-2-(trifluoromethyl)phenylhydrazinehydrochloride (Step 3)

[1644] The subtitle compound was prepared according to the procedure ofExample 135 using 4-(methylsulfonyl)-2-(trifluoromethyl)aniline insteadof 4-(Methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1645][5-[4-(2-Furyl)phenyl]1-[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole(Step 4)

[1646] The title compound was prepared according to the procedure ofExample 60 using 4-(methylsulfonyl)-2-(trifluoromethyl)phenylhydrazinehydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazinehydrochloride in step 2.

[1647]¹H-NMR (CDCl₃) δ: 8.40 (s, 1H), 8.16 (d, J=8 Hz, 1H), 7.61 (d, J=9Hz, 2H), 7.53 (d, J=8 Hz, 1H), 7.48 (s, 1H), 7.15 (d, J=8 Hz. 2H), 6.86(s, 1H), 6.71-6.68 (m, 1H), 6.48 (s, 1H), 3.12 (s, 3H).

[1648] Anal. Calcd. for. C₂₂H₁₄F₆N₂O₃S, 0.05Hexane, 0.4H₂O: C, 52.23; H,3.02; N, 5.49. Found: C, 52.37; H, 2.94; N, 5.09.

[1649] mS (EI): m/z 500 (M⁺)

Example 148

[1650]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methoxybenzenesulfonamide

[1651] 3-Methoxyacetanilide (Step 1)

[1652] To a stirred solution of m-anisidine (12.3 g, 0.1 mol) in THF (80mL) was added acetic anhydride (11.3 mL, 0.12 mol) at 0° C. The mixturewas stirred at room temperature for 30 minutes. The reaction mixture waswashed with water (50 mL), brine (30 mL), dried over MgSO₄, andconcentrated in vacuo. The resulting solid was recrystallized frommethylene chloride-hexane to give the subtitle compound (15.9 g, 96.4%yield).

[1653]¹H-NMR (CDCl₃) δ: 7.43 (brs, 1H), 7.27-7.26 (m, 1H), 7.20 (dd,J=8, 8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 6.65 (dd, J=2, 8 Hz, 1H), 3.79 (s,3H), 2.16 (s, 3H).

[1654] 4-Acetamido-2-methoxybenzenesulfonamide (Step 2)

[1655] The subtitle compound was prepared according to the procedure ofExample 137 using 3-methoxyacetanilide instead of 3-fluoroacetanilide instep 1.

[1656] 4-Amino-2-methoxybenzenesulfonamide (Step 3)

[1657] The subtitle compound was prepared according to the procedure ofExample 137 using 4-acetamido-2-methylbenzenesulfonamide instead of4-acetamido-2-fluorobenzenesulfonamide in step 2.

[1658]¹H-NMR (DMSO-d₆) δ: 7.34 (d, J=8 Hz, 1H), 6.57 (brs, 2H), 6.25 (d,J=2 Hz, 1H), 6.12 (dd, J=2, 8 Hz, 1H), 5.81 (brs, 2H), 3.77 (s, 3H).

[1659] 3-Methoxy-4-sulfamoylphenylhydrozine hydrochloride (step 4)

[1660] The subtitle compound was prepared according to the procedure ofExample 135 using 4-amino-2-methoxybenzenesulfonamide instead of4-(methylsulfonyl)-3-(trifluoromethyl)aniline in step 3.

[1661]4-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methoxybenzenesulfonamide(Step 5)

[1662] The title compound was prepared according to the procedure ofExample 60, using 3-methoxy-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride instep 2.

[1663] mp: 206.7° C.

[1664]¹H-NMR (CDCl₃) δ: 7.85 (d, J=8 Hz, 1H), 7.69 (dd, J=2, 8 Hz, 2H),7.51 (d, J=2 Hz, 1H), 7.26 (d, J=8 Hz, 2H), 7.16 (d J=2 Hz, 1H), 6.94(dd, J=2, 8 Hz, 1H), 6.80 (s, 1H), 6.73 (d, J=4 Hz, 1H), 6.51 (dd, J=2,4 Hz, 0.1H), 5.05 (brs, 2H), 3.91 (s, 3H).

[1665] Anal. Calcd. for. C₂₁H₁₆F₃N₃O₄S, 0.1H₂O: C, 54.22; H, 3.51; N,9.03. Found: C, 54.41; H, 3.73; N, 8.63.

[1666] mS (EI): m/z 463 (M⁺)

Example 149

[1667]2-Chloro-4-[5-[3-methyl-4-(4-thiazol)phenyl]-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide

[1668] The title compound was prepared according to the procedure ofExample 60 using 3-chloro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step2.

[1669] mp: 113.0-115.0° C.

[1670]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 7.79(d, J=2 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 7.27-7.22(m, 2H), 7.07 (d, J=8 Hz, 1H), 6.81 (s, 1H), 5.20 (brs, 2H), 2.47 (s,3H).

[1671] Anal. Calcd. for. C₂₀H₁₄ClF₃N₄O₂S₂, 0.4Hexane: C, 49.68; H, 3.47;N, 10.73. Found: C, 49.96; H, 3.84; N, 10.36.

[1672] mS (EI): m/z 498 (M⁺)

Example 150

[1673]3-Fluoro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1674] The title compound was prepared according to the procedure ofExample 60 using 2-fluoro-4-sulfamoylphenylhydrazine hydrochlorideinstead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step2.

[1675]¹H-NMR (CDCl₃) δ: 8.87 (d, J=2 Hz, 1H), 7.81-7.60 (m, 3H), 7.53(d, J=8 Hz, 1H), 7.38 (d, J=2 Hz, 1H); 7.22-7.21 (brs, 1H), 7.00 (d, J=8Hz, 1H), 6.83 (s, 1H), 5.39 (brs, 2H), 2.40 (s, 3H).

[1676] Anal. Calcd. for. C₂₀H₁₄F₄N₄O₂S₂, 0.3H₂O: C, 49.24; H, 3.02; N,11.48. Found: C, 49.51; H, 3.35; N, 11.12.

[1677] mS (EI): m/z 482 (M⁺)

Example 151

[1678]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-[4-(4-thiazolyl)phenyl]-1H-pyrrole

[1679] To a stirred solution of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole(0.318 g, 0.78 mmol, Example 35, step 3) in 1,4-dioxane (12 mL) wasadded 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithium chloride(0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0)(0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixturewas heated at reflux temperature for 3.5 hours. After cooling, volatileswere removed by evaporation. The residue was redissolved in ethylacetate (30 mL) and the whole washed with water and brine. After driedover MgSO₄ and concentration in vacuo. The crude mixture was purified byflash chromatography eluting with hexane/ethyl acetate (3/1). Theresulting solid was recrystallized from ethyl acetate-hexane to give thetitle compound (0.221 g, 68.8% yield).

[1680] mp: 215.0° C.

[1681]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 8.02 (d, J=9 Hz, 2H), 7.65(dd, J=7, 8 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.24 (d, J=9 Hz, 2H),6.99-6.88 (m, 2H), 6.56 (d, J=4 Hz, 1H), 6.16 (d, J=4 Hz, 1H), 3.15 (s,3H), 2.17 (s, 3H).

[1682] Anal. Calcd. for. C₂₁H₁₇FN₂O₂S₂, 0.5H₂O: C, 59.84; H, 4.30; N,6.65. Found: C, 59.57; H, 4.37; N, 6.36.

[1683] mS (EI): m/z 412 (M)

Example 152

[1684]5-[3-Fluoro-4-(methylsulfonylphenyl]-2-methyl-1-[3-methyl-4-(4-thiazolyl)phenyl]-1H-pyrrole

[1685] The title compound was prepared according to the procedure ofExample 151 using5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-[3-methyl-4-(4-thiazolyl)phenyl]-1H-pyrroleinstead of1-(4-Bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole(Example 39).

[1686] mp: 179.0-181.0° C.

[1687]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.72-7.63 (m, 2H), 7.45(d. J=2 Hz, 1H), 7.10-7.05 (m, 2H), 6.99-6.92 (m, 2H), 6.55 (d, J=4 Hz,1H), 6.14 (d, J=4 Hz, 1H), 3.17 (s, 3H), 2.47 (s, 3H), 2.16 (s, 3H).

[1688] Anal. Calcd. for. C₂₂H₁₉FN₂O₂S₂, 0.3H₂O: C, 61.18; H, 4.57; N,6.49. Found: C, 60.98; H, 4.55; N, 6.21.

[1689] mS (EI): m/z 426 (M⁺)

Example 153

[1690]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-[4-(4-thiazolyl)phenyl]-4-trifluoromethyl-1H-imidazole

[1691]N-[3-Fluoro-4-(methylsulfonyl)phenyl]-4-(bromophenyl)benzenecarboximidamide.(Step 1)

[1692] To a suspension of 3-fluoro-4-(methylsulfonyl)aniline (6.24 g, 33mmol) in toluene (100 mL) at 0° C. was added over 5 minutestrimethylaluminum (50.5 mL, 0.98 M solution in hexane, 49.5 mmol). Thereaction mixture was warmed to room temperature and stirred for 3.5hours. A solution of 4-bromobenzonitrile (12 g, 65.9 mmol) in toluene(60 mL) was added over 15 minutes and the reaction mixture heated to 70°C. After 20 hours, the reaction mixture was cooled to room temperatureand poured over a slurry of silicagel in chloroform-methanol (2:1, 750mL). After filtration, the residue was washed with a mixture ofmethylene chloride-methanol (2:1, 375 mL). The combined filtrates wereconcentrated in vacuo, and the resulting yellowish solid was washed withhexane-ether (2:1, 300 mL) to give the subtitle compound (12.78 g).

[1693] mS (EI): m/z 370 (M⁺)

[1694]2-(4-Bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole.(Step 2)

[1695] To a mixture ofN-[3-fluoro-4-(methylsulfonyl)phenyl]4-(bromophenyl)benzenecarboximidamide(12.77 g, 33 mmol) and sodium bicarbonate (5.54 g, 66 mmol) in2-propanol (250 mL) was added 3-bromo-1,1,1-trifluoroacetone (7.56 g,39.6 mmol). After the reaction mixture was heated to 80° C. for 17.5hours, the solvent was removed. The residue was redissolved in ethylacetate (200 mL) and washed with water (100 mL×2). The organic fractionswere combined, dried over MgSO₄, filtered, and concentrated in vacuo.The crude mixture was purified by flash chromatography eluting withhexane/ethyl acetate (4/1) to give the subtitle compound (3.05 g, 19.2%yield, via 2 steps).

[1696]¹H-NMR (DMSO-d₆) δ: 7.58 (d, J=8 Hz, 2H), 7.53 (dd, J=8, 9 Hz,1H), 7.35 (d, J=8 Hz, 2H), 6.98 (dd, J=2, 12 Hz, 1H), 6.60 (dd, J=2, 9Hz, 1H), 4.41 (d, J=12 Hz, 1H), 3.88 (d, J=12 Hz, 1H), 3.15 (s, 3H).

[1697] mS (EI): m/z 481 (M⁺)

[1698]2-(4-Bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.(Step 3)

[1699] A mixture of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole(3.05 g, 6.33 mmol) and p-toluenesulfonic acid monohydrate (0.300 g) intoluene (250 mL) was heated to reflux for 21 hours. The reaction mixturewas cooled and the solvent removed under reduced pressure. The cruderesidue was redissolved in methylene chloride (150 mL) and the wholewashed with water, aqueous NaHCO₃ (50 mL), and brine. After dried overMgSO₄, and concentrated in vacuo. The crude mixture was purified byflash chromatography eluting with hexane/ethyl acetate (3/1) to give thesubtitle compound (1.517 g, 51.8% yield).

[1700]¹H-NMR (CDCl₃) δ: 8.07 (dd, J=8, 8 Hz, 1H), 7.51 (d, J=8 Hz, 2H),7.52 (s, 1H), 7.27 (d, J=8 Hz, 2H), 7.2.6-7.16 (m, 2H), 3.29 (s, 3H).

[1701] mS (EI): m/z 462)

[1702]1-[3-Fluoro-4-(methylsulfonyl)phenyl)-2-[4-(4-thiazolyl)phenyl]-4-trifluoromethyl-1H-imidazole.(Step 4)

[1703] To a stirred solution of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]4-trifluoromethyl-H-imidazole(0.361 g, 0.78 mmol) in 1,4-dioxane (12 mL) was added4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithiun chloride (0.083g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g,0.078 mmol) at room temperature under nitrogen. The mixture was heatedat reflux temperature for 3 hours. After cooling, volatiles were removedby evaporation. The residue was redissolved in ethyl acetate (30 mL) andthe whole washed with water and brine. After dried over MgSO₄ andconcentration in vacuo. The crude mixture was purified by flashchromatography eluting with hexane/ethyl acetate (3/1). The resultingsolid was recrystallized from ethyl acetate-hexane to give the titlecompound (0.319 g, 87.6% yield).

[1704] mp: 112.5-115.0° C.

[1705]¹H-NMR (CDCl₃) δ: 8.89 (d, J=2 Hz, 1H), 8.06 (dd, J=8, 9 Hz,0.1H), 7.94 (d, J=8 Hz, 2H), 7.63 (d, J=2 Hz, 1H), 7.54 (d, J=1 Hz, 1H),7.47 (d, J=8 Hz, 2H), 7.27-7.19 (m, 2H), 3.28 (s, 3H).

[1706] Anal. Calcd. for. C₂₀H₁₃F₄N₃O₂S₂, 0.7H₂O: C, 50.04; H, 3.02; N,8.75. Found: C, 49.95; H, 3.00; N, 8.38.

[1707] mS (EI): m/z 467 (M⁺)

Example 154

[1708]2-Fluoro-4-[2-[4-(4-thiazol)phenyl]-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide

[1709]N-(3-Fluoro-4-sulfamoylphenyl)-4-(bromophenyl)benzenecarboximidamide.(Step 1)

[1710] The subtitle compound was prepared according to the procedure ofExample 153 (step 1) using 4-amino-2-fluorobenzenesulfonamide, insteadof 3-fluoro-4-(methylsulfonyl)aniline.

[1711] mS (EI): m/z 370 (M⁺−1)

[1712]4-[2-(4-Bromophenyl)-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazol-1-yl]-2-fluorobenzenesulfonamide.(Step 2)

[1713] The subtitle compound was prepared according to the procedure ofExample 153 (step 2) usingN-(3-fluoro-4-sulfamoylphenyl)-4-(bromophenyl)benzenecarboximidamide,instead ofN-[3-fluoro-4-(methylsulfonyl)phenyl]-4-(bromophenyl)benzenecarboximidamide.

[1714] mS (EI): m/z 483 (M⁺+2)

[1715]4-[2-(4-Bromophenyl)-4-hydroxy-4-trifluoromethyl-1H-imidazol-1-yl]-2-fluorobenzenesulfonamide. (Step 3)

[1716] The subtitle compound was prepared according to the procedure ofExample 153 (step 3) using4-[2-(4-bromophenyl)₄-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazol-1-yl]-2-fluorobenzenesulfonamideinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole.

[1717]¹H-NMR (CDCl₃) δ: 7.99 (dd, J=8, 9 Hz, 1H), 7.55 (d, J=1 Hz, 1H),7.50 (d, J=9 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.16-7.11 (m, 2H), 6.69 (s,2H).

[1718] mS (EI): m/z 463 (M⁺)

[1719]2-Fluoro-4-[2-[4-(4-thiazolyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide. (Step 4)

[1720] The title compound was prepared according to the procedure ofExample 153 (step 4) using4-[2-(4-bromophenyl)-4-hydroxy-4-trifluoromethyl-1H-imidazol-1-yl]-2-fluorobenzenesulfonamideinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.

[1721] mp: 130.0-133.0° C.

[1722]¹H-NMR (CDCl₃) δ: 8.88 (d, J=2 Hz, 1H), 7.99 (t, J=8 Hz, 1H), 7.92(d, J=9 Hz, 2H), 7.62 (d, J=2 Hz, 1H), 7.53 (d, J=1 Hz, 1H), 7.46 (d,J=9 Hz, 2H), 7.22-7.15 (m, 2H), 5.28 (brs, 2H).

[1723] Anal. Calcd. for. C₁₉H₁₂F₄N₄O₂S₂, 0.3hexane, 0.5H₂O: C, 49.02; H,3.26; N, 11.32. Found: C, 48.73; H, 3.13; N, 10.99.

[1724] mS (EI): m/z 468 (M⁺)

Example 155

[1725]1-3-Chloro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1726] 3-Chloro-4-(methylsulfonyl)phenylhydrazine hydrochloride (Step 1)

[1727] To a stirred suspension of 3-chloro-4-(methylsulfonyl)aniline(3.0 g, 15.0 mmol, Ish. K. Khanna et al., J. Med. Chem. 40, 1619 (1997))in 20% aqueous HCl (20 mL) was added dropwise a solution of sodiumnitrite (1.1 g, 16.0 mmol) in water (20 mL) below −5° C. After stirringfor 1 hour at that temperature, tin(II) chloride dihydrate in 20%aqueous HCl (20 mL) was added dropwise below −5° C. The resultingsuspension was stirred for 1 h at room tempetature. The mixture wasbasified with aqueous NaOH (pH=14) and extracted with CHCl₃ (200 mL×2),dried over MgSO₄, and concentarted in vacuo. The solid (5 g) wasdissolved in 10% methanolic HCl (30 mL), and volatiles were removed byevaporation. The residue was washed with ethanol to give the titlecompound (1.3 g, 34%).

[1728]¹H-NMR (DMSO-d₆) δ: 9.32 (br 1H), 7.89 (d, J=8.7 Hz, 1H), 7.20 (d,J=2.1 Hz, 1H), 7.02 (dd, J=8.7, 2.1 Hz, 1H), 3.29 (s, 3H).

[1729]1-[3-Chloro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.(Step 2)

[1730] The title compound was prepared according to the procedure ofExample 60 using [3-chloro-4-(methylsulfonyl)phenyl]hydrazinehydrochloride from step 1 instead of[3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride.

[1731] mp: 139-142° C.

[1732]¹H-NMR (CDCl₃) δ: 8.05 (d, J=8.6 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H),7.71 (d, J=8.2 Hz, 2H), 7.52 (s, 1H), 7.34-7.24 (m, 3H), 6.81 (s, 1H),6.75, (d, J=3.3 Hz, 1H), 6.52 (dd, J=3.3, 1.8 Hz, 1H), 3.28 (s, 3H).

[1733] Anal. Calcd. for C₂₁H₁₄N₂O₃F₃CIS: C, 54.03; H, 3.02; N, 6.00.Found: C, 53.79; H, 3.14; N, 5.92.

Example 156

[1734]5-[5-[4-(2-Furyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanol

[1735] 3-Hydroxymethyl-4-(methylthio)nitrobenzene. (Step 1)

[1736] To a solution of 4-chloro-3-(hydroxymethyl)nitrobenzene (20 g,0.10 mol) in DMSO (160 mL) and MeOH (80 mL), MeSNa (8.2 g, 0.12 mol) wasadded portionwise at 0° C. and the mixture was stirrred for 2 h at roomtemperature. The mixture was poured into ice water (300 mL) and theyellow precipitate was collected by filtration and washed with ether(150 mL) gave the title compound (21 g, quantitative).

[1737]¹H-NMR (DMSO-d₆) δ: 8.25 (d, J=2.5 Hz, 1H), 8.12 (dd, J=2.5, 8.7Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 5.70 (br, 1H), 4.51 (s, 2H), 2.60 (s,3H).

[1738] 3-Hydroxymethyl-4-(methylsulfonyl)nitrobenzene. (Step 2)

[1739] To a solution of 3-hydroxymethyl-4-(methylthio)nitrobenzene fromstep 1 (20 g, 0.10 mol) in CH₂Cl₂ (500 mL) and MeOH (100 mL), m-CPBA (74g, 0.30 mol) was added portionwise at 0° C. and the mixture was stirrredfor 16 h at room temperature. The mixture was added aqueous Na₂SO₃ (20 gin 200 mL of water) at 0° C. Organic layer was separated and washed withsaturated aqueous NaHCO₃ (300 mL), dried over MgSO₄, and concentarted invacuo gave the title compound (15.6 g, 65%).

[1740]¹H-NMR (DMSO-d₆) δ: 8.57 (d, J=2.5 Hz, 1H), 8.34 (dd, J=2.5, 8.6Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 5.88 (t, J=5.4 Hz, 1H), 5.00 (d, J=5.4Hz, 1H), 3.35 (s, 3H).

[1741] 3-Hydroxymethyl-4-(methylsulfonyl)aniline. (Step 3)

[1742] The title compound was prepared according to the procedure ofExample 60 using 3-hydroxymethyl-4-(methylsulfonyl)nitrobenzene fromstep 2 instead of 1-[3-fluoro-4-(methylsulfonyl)phenyl]hydradinehydrochloride.

[1743]¹H-NMR (DMSO-d₆) δ: 7.50 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.1 Hz,1H), 6.50 (dd, J=2.1, 8.6 Hz, 1H), 6.08 (br, 2H), 5.26 (t, J=5.6 Hz,1H), 4.73 (d, J=5.6 Hz, 2H), 3.06 (s, 3H).

[1744] 3-Hydroxymethyl-4-(methylsulfonyl)phenylhydrazine hydrochloride.(Step 4)

[1745] The title compound was prepared according to the procedure ofstep 1 of Example 155 using 3-hydroxymethyl-4-(methylsulfonyl)anilinefrom step 3 instead of 3-chloro-4-(methylsulfonyl)aniline.

[1746]¹H-NMR (DMSO-d₆) δ: 10.50 (br, 1H), 9.05 (br, 1H), 7.78 (d, J=8.7Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 6.95 (dd, J=2.3, 8.7 Hz, 1H), 4.84 (s,2H), 3.17 (s, 3H).

[1747]5-[5-[4-(2-Furyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanol.(Step 5)

[1748] The title compound was prepared according to the procedure ofExample 60 using 3-hydroxymethyl-4-(methylsulfonyl)phenylhydrazinehydrochloride from step 4 instead of[3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride.

[1749] mp: 135-150° C.

[1750]¹H-NMR (CDCl₃) o: 7.99 (d, J=8.6 Hz, 1H), 7.76 (d, J=2.3 Hz, 1H),7.69 (d, J=8.6 Hz, 2H), 7.51 (d, J=1.8 Hz, 1H), 7.35 (dd, J=2.3, 8.6 Hz,1H), 7.25 (d, J=8.6 Hz, 2H), 6.81 (s, 1H), 6.74 (d, J=3.5 Hz, 1H), 6.51(dd, J=1.8, 3.3 Hz, 1H), 4.95 (d, J=6.4 Hz, 2H), 3.17 (s, 3H).

[1751] Anal. Calcd. for C₂₂H₁₇N₂O₄F₃S: C, 57.14; H, 3.71; N, 6.06.Found: C, 56.47; H, 3.76; N, 5.91.

Example 157

[1752]5-[4-(2-Furyl)phenyl]-1-[3-methyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1753] 3-Methyl-4-(methylsulfonyl)phenylhydrazine hydrochloride. (Step1)

[1754] The title compound was prepared according to the procedure ofExample 155 using 3-methyl-4-(methylsulfonyl)aniline (Kugita, H. et al.Chem. Pharm. Bull. 10, 1001 (1962)) instead of3-chloro-4-(methylsulfonyl)aniline.

[1755]¹H-NMR (DMSO-d₆) δ: 10.59 (br, 2H), 8.96 (br. 1H), 7.78 (d, J=7.9Hz, 1H), 7.00-6.90 (m, 2H), 3.14 (s, 3H), 2.57 (s, 3H).

[1756]5-[4-(2-Furyl)phenyl]-1-[3-methyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.(Step 2)

[1757] The title compound was prepared according to the procedure ofExample 60 using 3-methyl-4-(methylsulfonyl)phenylhydrazinehydrochloride from step 1 instead of[3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride.

[1758] mp: 135-139° C.

[1759]¹H-NMR (CDCl₃) δ: 7.99 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.6 Hz, 2H),7.51 (m, 2H), 7.27-7.21 (m, 3H), 6.80 (s, 1H), 6.73 (d, J=3.5 Hz. 1H),6.50 (dd, J=1.8, 3.5 Hz, 1H), 3.09 (s, 3H), 2.71 (s, 3H).

[1760] Anal. Calcd. for C₂₂H₁₇N₂O₃F₃S: C, 59.19; H, 3.84; N, 6.27.Found: C, 59.20; H, 4.04; N, 6.18.

Example 158

[1761]1-[3-Chloro-4-(methylsulfonyl)phenyl]-5-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[1762]1-[3-Chloro-4-(methylsulfonyl)phenyl]-5-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole.

[1763] The title compound was prepared according to the procedure ofExample 60 using [3-chloro-4-(methylsulfonyl)phenyl]hydrazinehydrochloride from step 1 of Example 155 instead of[3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride,4,4,4-trifluoro-1-[4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione from step3 of Example 82 instead of4,4,4-trifluorro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1764] mp: 103-107° C.

[1765]¹H-NMR (CDCl₃) δ: 8.90 (d, J=1.8 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H),8.02-7.95 (m, 2H), 7.77 (d, J=2.1 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H),7.36-7.29 (m, 3H), 6.84 (s, 1H), 3.28 (s, 3H).

[1766] Anal. Calcd. for C₂₀H₁₃N₃O₂F₃ClS₂: C, 49.64; H, 2.71; N, 8.68.Found: C, 50.05; H. 3.15; N, 8.35.

Example 159

[1767]5-[4-(2-Furyl)phenyl]-1-[3-(methoxymetyl)-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole

[1768]5-[4-(2-Furyl)phenyl]-1-[3-(methoxymetyl)-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.

[1769] To a solution of5-[5-[4-(2-furyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanolfrom Example 156 (260 mg, 0.56 mmol) in THF (10 mL), NaH (27 mg, 0.67mmol) was added at 0° C. and the mixture was stirred for 0.5 h at roomtemperature. Iodomethane (0.050 mL, 0.67 mmol) was added at 0° C. andthe mixture was stirred for 4 h at room temperature. The mixture waspoured into water (30 mL), aqueous 2N HCl (5 mL) was added and extractedwith ethyl acetate (30 mL×2), dried over MgSO₄, and concentarted invacuo. The reaction mixture was purified by flash chromatography elutingwith ethyl acetate/hexane (1/4). The resulting solid was crystallizedfrom diisopropyl ether-hexane to give title compound (0.150 g, 56%).

[1770] mp: 142-143° C.

[1771]¹H-NMR (CDCl₃) δ: 8.03 (d, J=8.6 Hz, 1H), 7.73-7.65 (m, 3H), 7.51(s, 1H), 7.39 (dd, J=2.3, 8.6 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.80 (s,1H), 6.73 (d, J=3.3 Hz, 1H), 6.50 (dd, J=1.8, 3.3 Hz, 1H), 4.80 (s, 2H),3.38 (s, 3H), 3.16 (s, 3H).

[1772] Anal. Calcd. for C₂₃H₁₉N₂O₄F₃S: C, 57.98; H, 4.02; N, 5.88.Found: C, 57.92; H, 4.13; N, 5.78.

Example 160

[1773]N-[5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)benzyl]-N-methylaminehydrochloride

[1774] Step 1

[1775]1-[3-Chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole.

[1776] A mixture of5-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanol(170 mg, 0.37 mmol; Example 156) and triphenylphosphine (100 mg, 0.44mmol) in CCl₄ (10 mL) was refluxed for 16 h. After cooled to roomtemperature, the precipitate was separated by celite filteration andwashed with ether. The filtrate was purified by flash chromatographyeluting with ethyl acetate/hexane (1/4) to give title compound (0.073 g,41%).

[1777] mS (EI): m/z=480 (M⁺)

[1778] Step 2

[1779]N-[5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)benzyl]-N-methylaminehydrochloride.

[1780] To a solution of1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazolefrom step 1 (70 mg, 0.15 mmol) in THF (3.0 mL), methylamine (5.0 ml, 10mmol, 2.0 M in THF) and K₂CO₃ (200 mg, 1.5 mmol) was added at roomtemperature and stirred for 1 hour. The mixture was concentrated andethyl acetate (30 mL) was added, dried over MgSO₄, and concentarted invacuo. The solid was dissolved in 10% methanolic HCl (10 mL), andvolatiles were removed by evaporation. The residual solid wasrecrystallized from ethanol to give the title compound (45 mg, 59%).

[1781] mp: 270-272° C.

[1782]¹H-NMR (DMSO-d₆) δ: 9.20-8.90 (br 1H), 8.10-8.00 (m, 2H), 7.80 (s,1H), 7.74 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.45-7.35 (m, 3H),7.07 (d, J=3.3 Hz, 1H), 6.64 (s, 1H), 4.52 (s, 2H), 3.42 (s, 3H), 2.55(s, 3H).

[1783] Anal. Calcd. for C₂₃H₂₂N₃O₃F₃ClS: C, 53.96; H, 4.13; N, 8.21.Found: C, 53.39; H. 4.25; N, 8.01.

Example 161

[1784][5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanaminehydrochloride

[1785]2-[5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)benzyl]-1H-isoindole-1,3(2H)-dione.(Step 1)

[1786] A mixture of1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazolefrom step 1 of Example 160 (280 mg, 0.58 mmol) and potassium phthalimide(10 mg, 0.054 mmol) in DMF was heated at 90° C. for 1 hour. After cooledto room temperature, the mixture was poured into water (30 mL), andextracted with ether (30 mL×2), washed with water (30 mL) and brine (30mL), dried over MgSO₄, and concentarted in vacuo to give the titlecompound (240 mg, 70%).

[1787] mS (EI): m/z 591 (M⁺)

[1788][5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanaminehydrochloride. (Step 2)

[1789] A mixture of2-[5-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)benzyl]-1H-isoindole-1,3(2H)-dioneform step 1 (240 mg, 0.41 mmol) and hydradine monohydrate (110 mg, 2.2mmol) in EtOH (10 mL) was refluxed for 4 h. After colled to roomtemperature, concentrated and water (20 mL) was added and extracted withethyl acetate (30 mL×2) and washed with saturated aqueous NaHCO₃ (20mL), dried over MgSO₄, and concentarted in vacuo. The reaction mixturewas purified by flash chromatography eluting with CH₂Cl₂/MeOH (13/1).The resulting solid was dissolved in 10% methanolic HCl (10 mL), andvolatiles were removed by evaporation. The residual solid wasrecrystallized from ethanol-isopropyl ether to give the title compound(12 mg, 6%).

[1790] mp: 238-241° C.

[1791]¹H-NMR (CDCl₃) δ: 8.01 (d, J=8.6 Hz, 1H), 7.72-7.65 (m, 3H), 7.51(d, J=1.3 Hz, 1H), 7.32 (dd, J=2.1, 8.6 Hz, 1H), 7.27-7.24 (m, 2H), 6.81(s, 1H), 6.73 (d, J=3.5 Hz, 1H). 6.51 (dd, J=1.8, 3.5 Hz, 1H), 4.20 (s,2H), 3.23 (s, 3H).

[1792] Anal. Calcd. for C₂₂H₁₉N₃O₃F₃ClS: C, 53.07; H. 3.85: N. 8.44.Found: C, 50.58; H, 4.68; N, 7.46.

Example 162

[1793]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole

[1794]5-(4-Bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 1)

[1795] The title compound was prepared according to the procedure ofExample 60 using (Z)-1-[4-bromophenyl)-3-(dimethylamino)-2-propen-1-one(John T. Gupton et al., J. Org. Chem. 22, 4522 (1980)) instead of4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione. ¹H-NMR (CDCl₃) δ:7.88 (t, J=7.7 Hz, 1H), 7.77 (d. J=1.8 Hz, 1H), 7.54 (d, J=8.6 Hz, 2H).7.35 (dd, J=1.8, 10.7 Hz, 1H), 7.20-7.11 (m, 3H), 6.54 (d, J=1.8 Hz,1H), 3.24 (s, 3H).

[1796]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole.(Step 2)

[1797] The title compound was prepared according to the procedure ofExample 5 using5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazoleinstead of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide,2-furanboronic acid instead of 3-thienylboronic acid.

[1798] mp: 155-156° C.

[1799]¹H-NMR (CDCl₃) δ: 7.87, (t, J=7.7 Hz, 1H), 7.78 (d J=1.6 Hz, 1H),7.70 (d, J=8.6 Hz. 2H), 7.51 (d, J=1.8 Hz, 1H), 7.38 (dd, J=2.0, 10.9Hz, 1H), 7.30-7.20 (m, 3H), 6.73 (d. J=3.3 Hz, 1H), 6.56 (d, J=1.8 Hz,1H), 6.51 (dd, J=1.8, 3.3 Hz, 1H), 3.23 (s, 3H).

[1800] Anal. Calcd. for C₂₀H₁₅N₂O₃FS: C, 62.82; H, 3.95, N, 7.33. Found:C, 62.26; H, 4.16; N, 7.12.

Example 163

[1801]4-Cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-514-(2-furyl)phenyl]-1H-pyrazole

[1802]5-(4-Bromophenyl)-4-cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 1)

[1803] The title compound was prepared according to the procedure ofExample 60 using 2-(4-bromobenzoyl)-3-(dimethylmino)acrylonitrile(Field, George F. et al., DE 2330913) instead of4,4,4-trifluorro-1-[4-(2-furyl)phenyl]-1,3-butanedione.

[1804]¹H-NMR (CDCl₃) δ: 8.32 (s, 1H), 7.95 (dd, J=7.7, 8.6 Hz, 1H), 7.73(d, J=8.7 Hz, 2H), 7.55 (dd, J=2.0, 10.7 Hz, 1H), 7.45 (d, J=8.7 Hz,2H), 7.43-7.37 (m, 1H), 3.30 (s, ³H).

[1805]4-Cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-fury)phenyl]-1H-pyrazole.(Step 2)

[1806] The title compound was prepared according to the procedure ofExample 5 using5-(4-bromophenyl)-4-cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazoleinstead of4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide,2-furanboronic acid instead of 3-thienylboronic acid.

[1807] mp: 153-157° C.

[1808]¹H-NMR (CDCl₃) δ: 8.07 (s, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.77 (d,J=8.4 Hz, 2H), 7.54 (s, 1H), 7.42-7.34 (m, 3H), 7.22 (d, J=8.4 Hz, 1H),6.79 (d, J=3.3 Hz, 1H), 6.52 (s, 1H), 3.24 (s, 3H).

[1809] Anal. Calcd. for C₂₁H₁₄N₃O₃FS: C, 61.91; H, 3.46; N, 10.31.Found: C, 61.75; H, 3.69; N, 10.15.

Example 164

[1810]N-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl]-1H-pyrazol-4-yl]acetamide

[1811] (E)-1-(4-Bromophenyl)-3-(dimethylamino)-2-nitro-2-propen-1-one.(Step 1)

[1812] A mixture of 1-(4-bromophenyl)-2-nitroethanone (5.38 g, 0.022mol, Seter J. et al., Isr. J. Chem., 4, 7 (1966)) andN,N-dimethylformamide dimethylacetal (2.9 g, 0.024 mol) and cataliticamount of p-TsOH in THF (100 mL) was refluxed for 10 h. The mixture wascooled to room temperature and concentrated in vacuo. The reactionmixture was purified by flash chromatography eluting with ethylacetate/hexane (1/1) to give title compound (2.8 g, 43%).

[1813]¹H-NMR (CDCl₃) δ: 8.35 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.58 (d,J=8.6 Hz, 2H), 3.38 (s, 3H), 2.77 (s, 3H).

[1814]5-(4-Bromophenyl)-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-4-nitro-1H-pyrazole.(Step 2)

[1815] The title compound was prepared according to the procedure ofExample 0.60 using(E)-1-(4-bromophenyl)-3-(dimethylamino)-2-nitro-2-propen-1-one from step1 instead of 4,4,4-trifluorro-1-[4-(2-furyl)phenyl]-11,3-butanedione.

[1816]¹H-NMR (CDCl₃) δ: 8.77 (s, 1H), 7.91 (t, J=8.2 Hz, 1H), 7.70 (d,J=8.6 Hz, 2H), 7.58 (dd, J=2.0, 10.7 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H),7.32 (dd, J=1.5, 8.1 Hz, 1H), 3.33 (s, 3H).

[1817]4-Amino-5-(4-bromophenyl)-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole.(Step 3)

[1818] A mixture of5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]4-nitro-1H-pyrazolefrom step 2 (2.5 g, 5.7 mmol), iron powder (1.6 g, 28.4 mmol) and NH₄Cl(30 mg, 0.57 mmol) in EtOH:H₂O (40 mL: 10 mL) was refluxed for 1 h.After cooled to room temperature, the mixture was filtered by celite andwashed with ethyl acetate and the filtrate was concentrated. Wataer (50mL) was added to the resiual oil and extracted with ethyl acetate (80mL), dried over MgSO₄, and concentarted in vacuo gave the title-compound(1.9 g, 82%).

[1819]¹H-NMR (CDCl₃) δ: 7.81 (t, J=8.2 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H),7.52 (s, 1H), 7.27 (dd, J=2.1, 11.4 Hz, 1H), 7.13 (d. J=8.2 Hz, 2H),7.08 (dd, J=2.1, 8.6 Hz, 1H), 3.21 (s, 3H).

[1820]4-Amino-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl-1H-pyrazole.(Step 4)

[1821] The title compound was prepared according to the procedure ofExample 151 using 4-amino-5-(4-bromophenyl)-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole from step 3 instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[1822] mS (EI): m/z 414 (M⁺)

[1823]4-Amino-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl-1H-pyrazole.(Step 5)

[1824] To a solution of4-amino-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl-1H-pyrazolefrom step 5 (240 mg, 0.58 mmol) and pyridine. (0.15 mL, 1.7 mmol) inCH₂Cl₂ (20 mL), acetylchloride (0.050 mL, 0.69 mmol) was added at 0° C.and stirred for 1 h at room temperature. The mixture was washed withaqueous 2N HCl (20 mL), aqueous saturated NaHCO₃ (20 mL) and brine (20mL), dried over MgSO₄, and concentarted in vacuo. The reaction mixturewas purified by flash chromatography eluting with ethyl acetate/hexane(5/1). The resulting solid was recrystallized from ethyl acetate-hexaneto give title compound (0.140 g, 53%).

[1825] mp: 225.2° C.

[1826]¹H-NMR (DMSO-d₆) d: 9.43 (s, 1H), 9.21 (d, J=1.8 Hz, 1H), 8.29 (d,J=1.8 Hz, 1H), 8.10 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.80 (m, 1H),7.40-7.30 (m, 3H), 7.25-7.20 (m, 1H), 3.25 (s, 3H), 1.97 (s, 3H).

[1827] Anal. Calcd. for C₂₁H₁₇N₄O₃FS₂: C, 55.25; H, 3.75; N, 12.27.Found: C, 55.22; H, 3.98; N, 11.96.

Example 165

[1828]4-[3-Fluoro-4-(methylsulfonyl)phenyl-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone

[1829]3-(4-Bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-2(5H)-furanone.(Step 1)

[1830] The title compound was prepared according to the procedure ofExample 32 using 2-bromo-1-[3-fluoro-4-(methylsulfonyl)phenyl]ethanone(Lalezari, Iradj et al., J. Chem. Eng. Data, 11, 619 (1966)) instead of2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone, 4-bromophenylacetic acidinstead of 4-(3-thienyl)phenylacetic acid.

[1831]¹H-NMR (CDCl₃) δ: 7.99 (t, J=7.2 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H),7.32-7.25 (m, 3H), 7.19 (d, J=1.5, 10.2 Hz, 1H), 5.16 (s, 2H), 3.25 (s,3H).

[1832]4-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone.(Step 2)

[1833] The title compound was prepared according to the procedure ofExample 151 using3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-2(5H)-furanoneinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[1834] mp: 217.8° C.

[1835]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2.0 Hz, 1H), 8.02-7.94 (m, 3H), 7.63(d, J=2.0 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.33 (dd, J=1.5, 8.2 Hz, 1H),7.24 (dd, J=1.6, 10.5 Hz, 1H), 5.19 (s, 2H), 3.25 (s, 3H).

[1836] Anal. Calcd. for C₂₀H₁₄NO₄FS₂: C, 57.82; H, 3.40; N, 3.37. Found:C, 58.07; H, 3.63; N, 3.39.

Example 166

[1837]5,5-Dimethyl-4-[4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone

[1838] (Step 1)

[1839]3-(4-Bromophenyl)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone.

[1840] A mixture of[2-hydroxy-2-methyl-4-(methylsulfonyl)phenyl]propanone (1.5 g, 6.2 mmol,B. Cameron et al., WO 9619469), 4-bromophenylacetic acid (1.8 g, 8.1mmol), 1-cyclohexyl-3-(2-morphorynoethyl)carbodiimidemetho-p-toluenesulfonate (3.4 g, 8.1 mmol) and 4-(dimethylamino)pyridine(30 mg, 0.25 mmol) was stirred for 18 h at room temperature.1,8-Diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol) was added and themixture was refluxed for 3 h. After cooled to room temperature, H₂O (50mL) was added and extracted with CH₂Cl₂ (50 mL×2), washed with 2Naqueous HCl (50 mL), dried over MgSO₄, and concentarted in vacuo. Thereaction mixture was purified by flash chromatography eluting with ethylacetate/hexane (1/1) to give title compound (1.7 g, 65%).

[1841]¹H-NMR (CDCl₃) δ: 8.02 (d, J=8.6 Hz, 2H), 7.45-7.38 (m, 4H), 7.19(d, J=8.7 Hz, 2H), 3.12 (s, 3H), 1.61 (s, 6H).

[1842] Step 2

[1843]5,5-Dimethyl-4-[4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone.

[1844] The title compound was prepared according to the procedure ofExample 151 using3-(4-bromophenyl)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanonefrom step 1 instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[1845] mp: 215.8° C.

[1846]¹H-NMR (CDCl₃) δ: 8.85 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.7 Hz, 2H),7.83 (d, J=8.7, Hz, 2H), 7.55 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H),7.41 (d, J=8.7 Hz, 2H), 3.12 (s, 3H), 1.63 (s, 6H).

[1847] Anal. Calcd. for C₂₂H₁₉NO₄S₂: C, 62.10; H, 4.50; N, 3.29. Found:C, 61.81; H. 4.68; N, 3.26.

Example 167

[1848]2-Fluoro-4-[5-oxo-4-14-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-furanyl]benzenesulfonamide

[1849] 4-Acetyl-2-(fluoro)benzenesulfonamide. (Step 1)

[1850] To a solution of 4-acetyl-2-fluoroaniline (5.0 g, 32.6 mmol,Krueger, G et al., Arzneim Forsch, 34, 11a, 1612 (1984)) in conc-HCl(24.0 mL), sodium nitrate (2.9 g, 42.4 mmol) in water (10 mL) was addedat 0° C. After stirring for 1 h, the resultant yellow solution was addedslowly to the suspension of copper (II) chloride dihydrate (1.7 g, 9.8mmol) and sulfur dioxide (10 g, 156 mmol) in acetic acid (25 ml) at 0°C. The mixture was stirred for 30 min at 0° C. and poured into ice water(200 mL) and extracted with CH₂Cl₂ (80 mL×2). The extracts was cooled to0° C. and 25% aqueous ammonia (70 mL) was added slowly and stirred for 1h at room temperature. The mixture was concentrated and the residualsolid was suspended with ether and collectted by filteration to give thetitle compound (3.3 g, 46%).

[1851]¹H-NMR (DMSO-d₆) δ: 7.97-7.87 (m, 3H), 7.79 (br s, 2H), 2.63 (s,3H).

[1852] 4-Bromoacetyl-2-(fluoro)benzenesulfonamide. (Step 2)

[1853] To a suspension of 4-acetyl-2-(fluoro)benzenesulfonamide fromstep 1 (4.0 g, 18 mmol) in acetic acid (90 mL) was added dropwise asolution of bromine (2.9 g, 18 mmol) in acetic acid (10 mL) at 40° C.The mixture was heated at 70° C. for 4 h. After cooled to roomtemperature, the mixture was concentrated and the residual brown solidwas rrecrystallized from ethyl acetate-hexane to give the title compound(3.2 g, 60%).

[1854]¹H-NMR (DMSO-d₆) δ: 8.20-7.92 (m, 3H), 7.90 (br s, 2H), 5.00 (s,2H).

[1855]4-[4-(4-bromophenyl)-5-oxo-2,5-dihydro-3-furanyl]-2-(fluoro)benzenesulfonamide.

[1856] (Step 3)

[1857] The title compound was prepared according- to the procedure ofExample 32 using 4-bromoacetyl-2-(fluoro)benzenesulfonamide from step 2instead of [2-bromo-1-[4-methylsulfonyl)phenyl]ethanone,4-bromophenylacetic acid instead of 4-(3-thienyl)phenylacetic acid.

[1858] mS (EI): m/z 411 (M⁺)

[1859]2-Fluoro-4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-furanyl]benzenesulfonamide.(Step 4)

[1860] The title compound was prepared according to the procedure ofExample 151 using4-[4-(4-bromophenyl)-5-oxo-2,5-dihydro-3-furanyl]-2-(fluoro)benzenesulfonamideinstead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[1861] mp: 194.2° C.

[1862]¹H-NMR (DMSO-d₆) δ: 9.22 (d, J=10.5 Hz, 1H), 8.26 (d, J=1.6 Hz,1H), 8.06 (d, J=8.2 Hz, 2H), 7.83-7.72 (m, 3H), 7.52-7.42 (m, 3H), 7.35(dd, J=1.6, 8.2 Hz, 1H), 5.41 (s, 2H).

[1863] Anal. Calcd. for C₁₉H₁₃N₂O₄FS₂: C, 54.80; H, 3.15; N, 6.73.Found: C, 54.79; H, 3.34; N, 6.62.

Example 168

[1864]4-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]isoxazole

[1865]3-(4-Bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.(Step 1)

[1866] To a solution of1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone (1.50 g, 4.42mmol) in a mixture of ethanol (12 ml) and water (6 ml) were addedhydroxylamine hydrochloride (615 mg, 8.84 mmol) and anhydrous sodiumacetate (715 mg, 8.84 mmol) at room temperature. The mixture was heatedfor 2 h at 75° C. and then diluted with diethyl ether (200 ml), washedwith water (50 ml×2) and saturated sodium bicarbonate (50 ml×2), anddried over magnesium sulfate. Removal of solvent gave 1.56 g (˜100%) of1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone oxime as anorange solid.

[1867] To a solution of1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone oxime (1.56 g,4.42 mmol) in tetrahydrofuran (10 ml) was added dropwise 9.7 ml (9.70mmol) of 1 M lithium N,N-diisopropylamide in tetrahydrofuran and hexane,which was prepared from N,N-diisopropylamine and 1.6 M n-butyl lithiumin hexane, over 0.5 h at −78˜—50° C. After 1 h, a solution of N-acetylimidazole (584 mg, 5.31 mmol) in tetrahydrofuran (10 ml) was added tothe mixture at the same temperature. The resulting mixture was allowedto warm up to room temperature and stirred for further 1 h. Then, themixture was acidified with 2M hydrochloric acid (−30 ml) and extractedwith diethyl ether (150 ml). The separated organic layer was washed withsaturated sodium bicarbonate (50 ml×2) and water (50 ml), dried overmagnesium sulfate, and evaporated. The obtained oily residue waschromatographed on a column of silica gel (80 g) as eluting with ethylacetate/hexane (1/4) to afford 632 mg (36%) of the title compound as acolorless oil.

[1868]¹H-NMR (CDCl₃) δ: 7.50-7.40 (4H, m), 7.23-7.16 (1H, m), 6.94-6.79(2H, m), 4.43 (1H, s), 3.29 (1H, br s), 2.45 (3H, s), 1.31 (3H, s).

[1869] mS; 395 and 397 (M⁺).

[1870]3-(4-Bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole.(Step 2)

[1871] A mixture of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol(630 mg, 1.59 mmol) and p-toluenesulfonic acid monohydrate (274 mg, 1.59mmol) in methanol (10 ml) was refluxed for 2 h. The mixture wasevaporated, dissolved in ethyl acetate (100 ml), washed with saturatedsodium bicarbonate (50 ml×2), and dried over anhydrous sodium sulfate.Removal of solvent gave 583 mg (97%) of the title compound as a paleyellow oil.

[1872]¹H-NMR (CDCl₃) δ: 7.51-7.45 (2H, m), 7.34-7.20 (3H, m), 6.92-6.82(2H, m), 2.50 (3H, s), 2.45 (3H, s).

[1873] mS; 377 and 379 (M⁺).

[1874]3-(4-Bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.(Step 3)

[1875] To a solution of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole (580mg, 1.53 mmol) in dichloromethane (20 ml) was added m-chloroperbenzoicacid (70% purity, 1.13 g, 4.60 mmol) at 0° C. The mixture was allowed towarm to room temperature and stirred for 2 h. The excess peracid wasquenched with saturated sodium sulfite (˜2 ml) until the color ofKI-starch paper did not change. The mixture was diluted with diethylether (100 ml), washed with saturated sodium bicarbonate (50 ml×2), anddried over magnesium sulfate. Removal of solvent gave a colorless oilyresidue, which was chromatographed on a column of silica gel (60 g) aseluting with ethyl acetate/hexane (1/2) to afford 634 mg (−100%) of thetitle compound as a colorless foam.

[1876]¹H-NMR (CDCl₃) δ: 7.98 (1H, t, J=7.7 Hz), 7.56-7.50 (2H, m),7.30-7.24 (2H, m), 7.15-7.04 (2H, m), 3.29 (3H, s), 2.52 (3H, s).

[1877] mS; 409 and 411 (M⁺).

[1878]4-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]isoxazole.(Step 4)

[1879] A mixture of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole(219 mg, 0.53 mmol), tributyl(1,3-thiazol-4-yl)tin (200 mg, 0.53 mmol)and tetrakis(triphenylphosphine)palladium (62 mg, 0.053 mmol) in toluene(5 ml) was refluxed for 26 h. The mixture was evaporated and theobtained residue was chromatographed on a column of silica gel (40 g) aseluting with ethyl acetate/hexane (1/2) to give 198 mg of a white solid,which was recrystallized from ethyl acetate/hexane to afford 128 mg(58%) of the title compound.

[1880] m.p.: 130° C.

[1881]¹H-NMR (CDCl₃) δ: 8.90 (1H, d, J=2.0 Hz), 8.01-7.93 (3. H, m),7.62 (1H, d, J=1.8 Hz), 7.49-7.43 (2H, m), 7.17 (1H, dd, J=1.5 and 8.1Hz), 7.09 (1H, dd, J=1.5 and 10.5 Hz), 3.27 (3H, s), 2.53 (3H, s).

[1882] mS; 414 (M⁺).

Example 169

[1883]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole

[1884] [3-Fluoro-4-(methylsulfanyl)phenyl]methanol (Step 1).

[1885] The mixture of 3-fluoro-4-(methylsulfanyl)benzaldehyde (19.44 g,114.2 mmol) and sodium borohydride (2.1 g, 55.46 mmol) in methanol (200mL) was stirred at room temperature for 2 hour. Water was added to themixture, and the mixture was evaporated, diluted with ethyl acetate (300mL), washed with water (100 mL), dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/hexane (1/4) to provide the subtitle compound(19.91 g, 100% yield) as an oil.

[1886]¹H-NMR (CDCl₃) δ: 7.26-7.29 (m, 1H), 7.06-7.23 (m, 2H), 4.67 (brs, 2H), 2.47 (s, 13H).

[1887] 4-(Bromomethyl)-2-fluoro-1-(methylsulfanyl)benzene (Step 2).

[1888] The mixture of [3-fluoro-4-(methylsulfanyl)phenyl]methanol (9.00g, 52.26 mmol) and carbon tetrabromide (19.06 g, 57.49 mmol) in CH₂Cl₂(200 mL) was added triphenylphosphine (15.08 g, 57.49 mmol) at 0° C.After 1 hour, the mixture was concentrated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate/hexane (1/10) to provide the subtitle compound (12.16 g. 94%yield) as an oil.

[1889]¹H-NMR (CDCl₃) δ: 7.06-7.24 (m, 314), 4.44 (s, 2H), 2.47 (s, 3H).

[1890] 1-(4-Bromophenyl)-2-[3-fluoro-4-(methylsulfanyl)phenyl]1-ethanone(Step 3).

[1891] To the mixture of 4-bromobenzoyl chloride (10.81 g, 49.26 mmol),zinc (4.40 g, 67.24 mmol) and tetrakis(triphenylphosphine)palladium(0)(2.99 g, 2.586 mmol) in DME (250 mL) was added dropwise the solution of4-(bromomethyl)-2-fluoro-1-(methylsulfanyl)benzene (12.16 g, 51.72 mmol)in DME (120 mL) at room temperature. After 2.5 hour, the mixture wasfiltered through celite, the filtrate was evaporated, diluted with ethylacetate (300 mL), washed with water (100 mL), brine (100 mL), dried oversodium sulfate, and concentrated in vacuo. The residue was washed withethyl acetate-isopropylether, to give the subtitle compound (12.16 g,73% yield) as a solid.

[1892]¹H-NMR (CDCl₃) δ: 7.85 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H),7.21 (d, J=7.9 Hz, 1H), 6.93-7.01 (m, 2H), 4.21 (s, 2H), 2.45 (s, 3H).

[1893]1-(4-Bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone (Step4).

[1894] To a stirred solution of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfanyl)phenyl]-1-ethanone (1.91g, 5.636 mmol) in acetic acid (20 mL) was added lead tetraacetate (2.75g, 6.200 mmol) at room temperature. The mixture was heated at refluxtemperature for 2 hours, and cooled down to room temperature. Themixture was evaporated, diluted with ethyl acetate (200 mL), washed withsaturated NaHCO₃ solution (100 mL), water (100 mL), dried over MgSO₄,and concentrated in vacuo. To a stirred solution of the residue (1.81g,) in CH₂Cl₂ (10 mL) was added 3-chloroperoxybenzoic acid (1.88 g,7.643 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 1.5 hour. The mixture was poured into saturated, NaHCO₃solution (50 mL), extracted with ethyl acetate (150 mL). The organiclayer was washed with saturated NaHCO₃ solution (50 mL), water (50 mL),dried over MgSO₄ and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/hexane(1/2) to provide the subtitle compound (1.02 g, 49% yield) as a solid.

[1895]¹H-NMR (CDCl₃) δ: 7.93 (t, J=7.6 Hz, 1H), 7.86 (d, J=8.9 Hz, 2H),7.66 (d, J=8.7 Hz, 2H), 7.15-7.23 (m, 2H), 4.35 (s, 2H), 3.22 (s, 3H).

[1896]2-Acetoxy-1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone(Step 5).

[1897] The mixture of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone (1.02g, 2.748 mmol) and lead tetraacetate (1.34 g 3.023 mmol) in acetic acid(15 mL) was heated at reflux temperature for 8 hours, and cooled down toroom temperature. The mixture was evaporated, poured in to ethyl acetate(50 mL) and saturated NaHCO₃ solution (50 mL). The formed precipitatewas removed by filtration. The filtrate was extracted with ethyl acetate(100 mL), washed with water (50 mL), brine (50 mL), dried over MgSO₄,and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/hexane (1/2) toprovide the subtitle compound (743.7 mg, 63% yield) as a solid.

[1898]¹H-NMR (CDCl₃) δ: 7.97 (t, J=7.3 Hz, 1H), 7.79 (d. J=8.7 Hz, 2H),7.62 (d, J=8.7 Hz, 2H), 7.36-7.43 (m, 2H), 6.81 (s, 1H), 3.20 (s, 3H),2.23 (s, 3H).

[1899]4-(4-Bromophenyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1,3-oxazole(Step 6).

[1900] The mixture of2-acetoxy-1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone(743.7 mg, 1.733 mmol) and ammonium acetate (333.9 mg, 4.333 mmol) inacetic acid (15 mL) was heated at reflux temperature for 2.5 hours, andcooled down to room temperature. The mixture was evaporated, dilutedwith ethyl acetate (100 mL), washed with saturated NaHCO₃ solution (100mL×2), water (50 mL), brine (50 mL), dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash chromatography on silica geleluting with ethyl acetate/hexane (1/2) to provide the subtitle compound(447.1 mg, 63% yield) as a solid. ¹H-NMR (CDCl₃) δ: 7.92 (t, J=7.2 Hz,1H), 7.43-7.59 (m, 6H), 3.25 (s, 3H), 2.59 (s, 3H).

[1901] 5-[3-Fluoro-4-(methylsulfonyl)phenyl1-2-methyl-4-[4-(13-thiazol-4-yl)phenyl]-1,3-oxazole (Step 7).

[1902] The title compound was prepared according to the procedure ofExample 168 (step 4) useing4-(4-bromophenyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1)₃-oxazoleinstead of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[1903] mp: 196-197° C.

[1904]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.2 Hz, 2H),7.91 (t, J=8.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.63 (d, J=1.8 Hz, 1H),7.58 (dd, J=1.5, 8.2 Hz, 1H), 7.50 (dd, J=1.5, 11.2 Hz, 2H), 3.24 (s,3H), 2.61 (s, 3H).

[1905] Anal. Calcd. for C₂₀H₁₅N₂O₃F₁S₂: C, 57.96; H, 3.65; N, 6.76.Found: C, 57.83; H, 3.76; N, 6.65.

Example 170

[1906]4-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]isoxazole

[1907]1-(4-Bromo-3-methylphenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone.(Step 1)

[1908] The title compound was prepared according to the procedure ofstep 1 in the Example 169 using 4-bromo-3-methylbenzoyl chloride, whichwas prepared according to the literature (G. Cignarella et al., J.Pharmaco. Ed. Sci., 1983, 38, 187-198.), instead of 4-bromobenzoylchloride.

[1909]¹H-NMR (CDCl₃) δ: 7.84 (1H, s), 7.64-7.62 (2H, m), 7.23 (1H, t,J=7.9 Hz), 7.01-6.92 (2H, m), 4.21 (2H, s), 2.46 (3H, s), 2.45 (3H, s).

[1910]3-(4-Bromo-3-methylphenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.(Step 2)

[1911] The title compound was prepared according to the procedure ofstep 1 in the Example 168 using1-(4-bromo-3-methylphenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone,instead of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone.

[1912]¹H-NMR (CDCl₃) δ: 7.54 (1H, d, J=2.1 Hz), 7.44 (1H, d, J=8.4 Hz),7.22-7.15 (2H, m), 6.93-6.79 (2H, m), 4.43 (1H, s), 3.49 (1H, br s),2.44 (3H, s), 2.34 (3H, s), 1.30 (3H, s).

[1913]3-(4-Bromo-3-methylphenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole.(Step 3)

[1914] The title compound was prepared according to the procedure ofstep 2 in the Example 168 using3-(4-bromo-3-methylphenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol,instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.

[1915]¹H-NMR (CDCl₃) δ: 7.47 (1H, d, J=8.2 Hz), 7.42 (1H, d. J=2.0 Hz),7.22 (1H, d, J=7.7 Hz), 6.98 (1H, dd, J=2.1 and 8.2 Hz), 6.92-6.84 (2H,m), 2.50 (3H, s), 2.45 (3H, s), 2.36 (3H, s).

[1916] 3-(4-Bromo-3,methylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.(Step 4)

[1917] The title compound was prepared according to the procedure ofstep 3 in the Example 168 using3-(4-bromo-3-methylphenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole,instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole.

[1918]¹H-NMR (CDCl₃) δ: 7.97 (1H, t, J=7.7 Hz), 7.51 (1H, d, J=8.2 Hz),7.40 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.5 and 8.1 Hz), 7.07 (1H, dd,J=1.3 and 10.4 Hz), 6.92 (1H, dd, J=1.6 and 8.2 Hz), 3.27 (3H, s), 2.52(3H, s), 2.39 (3H, s).

[1919]4-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]isoxazole.(Step 5)

[1920] The title compound was prepared according to the procedure ofstep 4 in the Example 168 using 3-(4-bromo-3-methylphenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole, instead of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[1921] m.p.: 99.5° C. (from dichloromethane/diisopropyl ether/hexane)

[1922]¹H-NMR (CDCl₃) δ: 8.90 (1H, d, J=2.0 Hz), 7.96 (1H, t, J=7.6 Hz),7.60 (1H, d, J=8.1 Hz), 7.46 (1H, br s), 7.40 (1H, d, J=2.0 Hz),7.20-7.08 (3H, my, 3.28 (3H, s), 2.53 (3H, s), 2.45 (3H, s).

[1923] mS; 428 (M⁺).

Example 171

[1924]4-{5-Methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide

[1925] 1-(4-Bromophenyl)-2-phenylethanone. (Step 1)

[1926] The title compound was prepared according to the procedure ofstep 1 in the Example 169 using benzyl bromide and4-bromo-3-methylbenzoyl chloride, instead of 4-bromobenzoyl chloride.

[1927]¹H-NMR (CDCl₃) δ: 7.90-7.83 (2H, m), 7.62-7.56 (2H, m), 7.38-7.22(5H, m), 4.25 (2H, s).

[1928] 3-(4-Bromophenyl)-5-methyl-4-phenyl-4,5-dihydro-5-isoxazolol.(Step 2)

[1929] The title compound was prepared according to the procedure ofstep 1 in the Example 168 using 1-(4-bromophenyl)-2-phenylethanone,instead of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone.

[1930] m.p.; 153° C. (from ethyl acetate/hexane)

[1931]¹H-NMR (CDCl₃) δ: 7.51-7.27 (7H, m), 7.17-7.08 (2H, m), 4.47 (1H,s), 3.12 (1H, s), 1.28 (3H, s).

[1932] 3-(4-Bromophenyl)-5-methyl-4-phenylisoxazole. (Step 3)

[1933] The title compound was prepared according to the procedure ofstep 2 in the Example 168 using3-(4-bromophenyl)-5-methyl-4-phenyl-4,5-dihydro-5-isoxazolol, instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.

[1934]¹H-NMR (CDCl₃) δ: 7.52-7.13 (9H, m), 2.45 (3H, s).

[1935] 4-[3-(4-Bromophenyl)-5-methyl-4-isoxazolyl]benzenesulfonamide.(Step 4)

[1936] To stirred chlorosulfonic acid (5 ml) was added3-(4-bromophenyl)-5-methyl-4-phenylisoxazdle (469 mg, 1.49 mmol) at −78°C. The mixture was allowed to warm up to room temperature and stirredfor further 1 h. The resulting black mixture was poured into ice-conc.ammonia water (200 ml) carefully and extracted with ethyl acetate (150ml). The organic layer was washed with water (50 ml×2), dried overanhydrous sodium sulfate, and evaporated. The obtained residue waschromatographed on a column of silica gel (60 g) as eluting with ethylacetate/hexane (1/1) to afford 512 mg (87%) of the title compound as afoam.

[1937]¹H-NMR (CDCl₃) δ: 7.98-7.91 (2H, m), 7.52-7.46 (2H, m), 7.34-7.24(4H, m), 4.97 (2H, br s), 2.49 (3H, s).

[1938]4-{5-Methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide.(Step 5)

[1939] The title compound was prepared according to the procedure ofstep 4 in the Example 168 using4-[3-(4-bromophenyl)-5-methyl-4-isoxazolyl]benzenesulfonamide, insteadof3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[1940] m.p.: 112-115° C. (from ethyl acetate/hexane)

[1941]¹H-NMR (CDCl₃) δ: 8.88 (1H, d, J=2.0 Hz), 7.97-7.88 (4H, m), 7.59(1H, d, J=2.0 Hz), 7.50-7.43 (2H, m), 7.39-7.32 (2H, m), 4.89 (2H, brs), 2.50 (3H, s).

[1942] mS; 397 (M+).

Example 172

[1943]2-Fluoro-4-{5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide

[1944] 1-(4-Bromophenyl)-2-(3-fluorophenyl)ethanone. (Step 1)

[1945] The title compound was prepared according to the procedure ofstep 1 in the Example 169 using 3-fluorobenzyl bromide and4-bromobenzoyl chloride.

[1946]¹H-NMR (CDCl₃) δ: 7.89-7.83 (2H, m), 7.65-7.59 (2H, m), 7.34-7.25(1H, m), 7.06-6.92 (3H, m), 4.25 (2H, s).

[1947]3-(4-Bromophenyl)-4-(3-fluorophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.(Step 2)

[1948] The title compound was prepared according to the procedure ofstep 1 in the Example 168 using1-(4-bromophenyl)-2-(3-fluorophenyl)ethanone, instead of1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone.

[1949]¹H-NMR (CDCl₃) δ: 7.50-7.26 (5H, m), 7.05-6.82 (3H, m), 4.46 (1H,s), 3.16 (1H, br s), 1.30 (3H, s).

[1950] 3-(4-Bromophenyl)-4-(3-fluorophenyl)-5-methylisoxazole. (Step 3)

[1951] The title compound was prepared according to the procedure ofstep 2 in the Example 168 using3-(4-bromophenyl)-4-(3-fluorophenyl)-5-methyl-4,5-dihydro-5-isoxazolol,instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.

[1952]¹H-NMR (CDCl₃) δ: 7.50-7.26 (5H, m), 7.11-6.85 (3H, m), 2.46 (3H,s).

[1953]2-[3-(4-Bromophenyl)-5-methyl-4-isoxazolyl]-4-fluorobenzenesulfonamideand4-[3-(4-Bromophenyl)-5-methyl-4-isoxazolyl]-2-fluorobenzenesulfonamide.(Step 4)

[1954] To stirred chlorosulfonic acid (5 ml) was added3-(4-bromophenyl)-4-(3-fluorophenyl)-5-methylisoxazole (618 mg, 1.86mmol) at −78° C. The mixture was allowed to warm up to 70° C. andstirred for further 1 h. The resulting black mixture was poured intoice-conc. ammonia water (200 ml) carefully and extracted with ethylacetate (150 ml). The organic layer was washed with water (50 ml×2),dried over anhydrous sodium sulfate, and evaporated. The obtainedresidue was chromatographed on a column of silica gel (60 g)-as elutingwith ethyl acetate/hexane (1/1) to afford, first, 307 mg (40%) of2-[3-(4-bromophenyl)-5-methyl-4-isoxazolyl]-4-fluorobenzenesulfonamideas a pale yellow solid.

[1955]¹H-NMR (CDCl₃) δ: 8.23 (1H, dd, J=5.4 and 8.9 Hz), 7.46-7.40 (2H,m), 7.33-7.25 (3H, m), 7.04 (1H, dd, J=2.6 and 8.4 Hz), 4.52 (2H, br s),2.33 (3H, s).

[1956] The second fractions gave 304 mg (40%) of4-[3-(4-bromophenyl)-5-methyl-4-isoxazolyl]-2-fluorobenzenesulfonamideas a colorless oil.

[1957]¹H-NMR (CDCl₃) δ: 7.91 (1H, dd, J=7.6 and 8.4 Hz), 7.55-7.48 (2H,m), 7.29-7.23 (2H, m), 7.09-7.00 (2H, m), 5.30 (2H, br s), 2.50 (3H, s).

[1958]2-Fluoro-4-{5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide.(Step 5)

[1959] The title compound was prepared according to the procedure ofstep 4 in the Example 168 using4-[3-(4-bromophenyl)-5-methyl-4-isoxazolyl]-2-fluorobenzenesulfonamide,instead of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[1960] m.p.: 216° C. (from ethyl acetate/hexane)

[1961]¹H-NMR (DMSO-d₆) δ: 9.11 (1H, d, J=1.8 Hz), 8.16 (1H, d, J=1.8Hz), 7.98-7.92 (2 H, m), 7.70 (1H, t, J=7.9 Hz), 7.62 (2H, br s),7.37-7.31 (2H, m), 7.28 (1H, dd, J=1.5 and 11.2 Hz), 7.10 (1H, dd, J=1.6and 8.1 Hz), 2.40 (3H, s).

[1962] mS; 415 (M⁺).

Example 173

[1963]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole

[1964]1-(4-Bromo-3-methylphenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone(Step 1).

[1965] To a stirred solution of1-(4-bromo-3-methylphenyl)-2-[3-fluoro-4-(methylsulfanyl)phenyl]-1-ethanone(1.50 g, 4.246 mmol) in CH₂Cl₂ (50 mL) was added 3-chloroperoxybenzoicacid (2.62 g, 10.62 mmol) at 0° C. The mixture was allowed to warm toroom temperature and stirred for 1.5 hour. The mixture was poured intosaturated NaHCO₃ solution (50 mL), extracted with ethyl acetate (100mL). The organic layer was washed with water (50 mL), brine (50 mL),dried over MgSO₄ and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with ethyl acetate/hexane(1/2) to provide the subtitle compound (1.21 g, 74% yield) as a solid.

[1966]¹H-NMR (CDCl₃) δ: 7.93 (t, J=7.6 Hz, 1H), 7.85 (s, 1H), 7.67 (s,2H), 7.15-7.22 (m, 2H), 4.34 (s, 2H), 3.22 (s, 3H), 2.48 (s, 3H).

[1967]2-Acetoxy-1-(4-bromo3-methylphenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone(Step 2).

[1968] The title compound was prepared according to the procedure ofExample 169 (step 5).

[1969]¹H-NMR (CDCl₃) δ: 7.96 (t, J=7.7 Hz, 1H), 7.78 (s, 2H), 7.59-7.65(m, 2H), 7.35-7.43 (m, 2H), 6.82 (s, 1H), 3.20 (s, 3H), 2.44 (s, 3H),2.23 (s, 3H).

[1970]4-(4-Bromo-3-methylphenyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1,3-oxazole(Step 3).

[1971] The title compound was prepared according to the procedure ofExample 169 (step 6).

[1972]¹H-NMR (CDCl₃) δ: 7.91 (t, J=7.6 Hz, 1H), 7.39-7.79 (m, 5H), 3.25(s, 3H), 2.59 (s, 3H), 2.43 (s, 3H).

[1973]5-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole(Step 4).

[1974] The title compound was prepared according to the procedure ofExample 168

[1975] mp: 177-178° C.

[1976]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2.0 Hz, 1H), 7.91 (t, J=7.4 Hz, 1H),7.69 (d, J=7.9 Hz, 1H), 7.46-7.61 (m, 4H), 7.42 (d, J=2.0 Hz, 1H), 3.25(s, 3H), 2.61 (s, 3H), 2.50 (s, 3H).

[1977] Anal. Calcd. for C₂₁H₁₇N₂O₃F₁S₂: C, 58.86; H. 4.00; N, 6.54.Found: C, 58.51; H, 4.15; N, 6.43.

Example 174

[1978]2-Fluoro-4-[5-[3-hydroxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1979]4,4,4-Trifluoro-1-[3-hydroxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 1)

[1980] To a stirred solution of4,4,4-trifluoro-1-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(395 mg, 1.2 mmol) in DMF (6 ml) was added sodium thiomethoxide (420 mg,6.0 mmol) and the mixture was heated at 120° C. for 3 hours. The mixturewas cooled down to room temperature, and poured into water. The wholewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo to give titlecompound (378 mg, 99% yield).

[1981]¹H-NMR (DMSO-d₆) δ: 10.92 (s, 1H), 9.24 (d, J=2 Hz, 1H), 8.36 (d,J=2 Hz, 1H), 8.16 (d, J=8 Hz, 1H), 7.53-7.45 (m, 2H), 6.27 (s, 1H).

[1982]2-Fluoro-4-[5-[3-hydroxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 2)

[1983] The title compound was prepared according to the procedure ofExample 0.60 using4,4,4-trifluoro-1-[3-hydroxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione, andusing (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1984] mp: 224-226° C.

[1985]¹H-NMR (CDCl₃) δ: 8.97 (d, J=2 Hz, 1H), 7.85-7.79 (m, 1H), 7.69(d, J=2 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.37 (dd, J=11, 2 Hz, 1H), 7.19(dd, J=8, 2 Hz, 1H), 6.98 (d, J=2 Hz, 1H), 6.80 (s, 1H), 6.71 (dd, J=8,2 Hz, 1H), 5.35 (s, 2H).

[1986] Anal. Calcd. for C₁₉H₁₂F₄N₄O₃S₂ {fraction (1/10)}Hexane+{fraction (1/10)}H₂O: C, 47.57; H, 2.77; N, 11.32. Found: C,47.61; H, 2.91; N, 10.93.

Example 175

[1987]2-Fluoro-4-[5-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1988] The title compound was prepared according to the procedure ofExample 107 using (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochlorideinstead of (2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1989] mp: 97-99° C.

[1990]¹H-NMR (CDCl₃) δ: 8.84 (d, J=2 Hz, 1H), 8.29 (d, J=8 Hz, 1H), 8.07d, J=2 Hz, 1H), 7.87-7.81 (m, 1H), 7.38 (dd, J=11.2 Hz, 1H), 7.20 (dd,J=9, 1 Hz, 1H), 6.93-6.89 (m, 2H), 6.84 (s, 1H), 5.31 (s, 2H), 3.88 (s,3H).

[1991] Anal. Calcd. for C₂₀H₁₄F₄N₄O₃S₂. Ethyl Acetate: C, 49.14; H,3.78; N, 9.55. Found: C, 48.84; H, 3.63; N, 9.81.

Example 176

[1992]2-Fluoro-4-[5-[4-(1,3-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[1993]4,4,4-Trifluoro-1-[4-bromo-3-(trifluoromethyl)phenyl]-1,3-butanedione(Step 1)

[1994] The title compound was prepared according to the procedure ofExample 94 (step 3) using1-[4-bromo-3-(trifluoromethyl)phenyl]-1-ethanone instead of1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone. The compound was used for nextreaction without purification.

[1995]2-Fluoro-4-[5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 2)

[1996] The title compound was prepared according to the procedure ofExample 60 using4,4,4-trifluoro-1-[4-bromo-3-(trifluoromethyl)phenyl]-1,3-butanedioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]-1,3-butanedione, andusing (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[1997]¹H-NMR (DMSO-d₆) δ: 7.96-7.86 (m, 5H), 7.63 (dd, J=11, 2 Hz, 1H),7.49-7.36 (m, 3H).

[1998]2-Fluoro-4-[5-[4-(1,3-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 3)

[1999] To a stirred solution of2-fluoro-4-[5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(308 mg, 0.58 mmol) in dioxane (5 ml) was added4-(tributylstannyl)thiazole (260 mg, 0.70 mmol),tetrakis(triphenylphosphine)palladium (67 mg, 0.058 mmol), lithiumchloride (61 mg, 1.45 mmol), and the mixture was heated at refluxtemperature for 16 hours. The reaction mixture was cooled down to roomtemperature, and diluted with ethyl acetate. The whole was washed withsaturated potassium fluoride aqueous solution, and the precipitate wasremoved by filteration through celite. The resulting solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography eluting with ethyl acetate-hexane (1:2) to givetitle compound (56 mg, 18% yield).

[2000] mp: 140-142° C.

[2001]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 7.90-7.84 (m, 1H), 7.78(d, J=2 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.56 (d, J=2 Hz, 1H), 7.42-7.40(m, 1H), 7.37, (d, J=2 Hz, 1H), 7.14 (dd. J=9, 2 Hz, 1H), 6.90 (s, 1H),5.57 (s, 2H).

[2002] Anal. Calcd. for C₂₀H₁₁F₇N₄O₂S₂ {fraction (1/10)} Hexane: C,45.39; H, 2.29; N, 10.28. Found: C, 45.25; H, 2.28; N, 10.17.

Example 177

[2003]4-{2-Ethyl-4-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole

[2004] 1-(3-Ethyl-4-hydroxyphenyl)-1-ethanone (Step 1)

[2005] To a stirred solution of 2-ethylphenol (1 g, 106.4 mmol) incarbon disulfide (30 ml) was added aluminum chloride (30 g, 225 mmol)portionwise at 0° C. Then, acetyl chloride (8.4 ml, 118.1 mmol) wasadded, and the mixture was heated at reflux temperature for 16 hours.The reaction mixture was cooled down to room temperature, and pouredinto ice. The whole was extracted with diethyl ether. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was recystallized with hexane-toluene to give title compound(9.24 g, 53% yield).

[2006]¹H-NMR (CDCl₃) δ: 7.82 (s, 1H), 7.74 (dd, J=8, 2 Hz, 1H), 6.88(dd, J=8, 5 Hz, 1H), 2.70 (q, J=8 Hz, 2H), 2.58 (d, J=2 Hz, 3H), 1.26(t, J=8 Hz, 3H).

[2007] 1-(4-[[tert-Butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone(Step 2)

[2008] To a stirred solution of 1-(3-ethyl-4-hydroxyphenyl)-1-ethanone(9.24 g, 56.27 mmol) in DMF (60 ml) was added tert-butyldimethylsilylchloride (9.33 g, 61.9 mmol), imidazole (4.6 g, 67.52 mmol), and themixture was stirred at room temperature for 3 hours. The reactionmixture was poured into water. The whole was extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was fractionally distilled underreduced pressure (180° c., 0.5 mmHg) to give title compound (12.3 g, 78%yield).

[2009]¹H-NMR (CDCl₃) δ: 7.80 (d, J=2 Hz. 1H), 7.71 (dd, J=8, 3 Hz, 1H),6.8; (d, J=8 Hz, 1H), 2.65 (q, J=8 Hz, 2H), 2.55 (s, 3H), 1.21 (t, J=8Hz, 3H), 1.02 (s, 9H), 0.27 (s, 6H).

[2010]1-(4-[[tert-Butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-4,4,4-trifluoro-1,3-butanedione(Step 3)

[2011] To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (1.79g, 11.1 mmol) in THF (37 ml) was added n-butyl lithium (1.52 M solutionin hexane; 7.3 ml, 11.1 mmol) dropwise at 0° C., and the mixture wasstirred at 0° c for 30 minutes, then cooled at −78° C. A solution of1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone (2.57 g,9.23 mmol) in THF (40 ml) was added dropwise, and the mixture wasstirred at −78° c for 1 hour. 1-(Trifluoroacetyl)imidazole (2.0 g, 12.2mmol) was added, and the mixture was stirred at −78° c for 3 hours, andquenched with water., The reaction mixture was warmed up to roomtemperature, and diluted with ethyl acetate. The whole was extractedwith ethyl acetate. The organic layer was washed with brine, dried over.MgSO₄, and concentrated in vacuo. The residue was used for next reactionwithout further purification. (3.45 g, 99% yield).

[2012]2-Ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(Step 4)

[2013] To a stirred solution of1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-4,4,4-trifluoro-1,3-butanedione(749 mg, 2.0 mmol) in ethanol (25 ml) was added(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride (530 mg, 2.2mmol), and the mixture was heated at reflux temperature for 16 hours.The reaction mixture was cooled down to room temperature, and pouredinto water. The whole was extracted with ethyl acetate. The organiclayer was washed with brine, dried over MgSO₄, and concentrated invacuo. The residue was dissolved in THF (5 ml). Tetrabutylammoniumfluoride (1.0 M solution in THF; 2.5 ml, 2.5 mmol) was added, and themixture was stirred for 1 hour. Then, the reaction mixture was pouredinto water. The whole was extracted with ethyl acetate. The organiclayer was washed with brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography eluting withethyl acetate-hexane (1:2) to give title compound (140 mg, 16% yield).

[2014]¹H-NMR (DMSO-d₆) δ: 9.83 (s, 1H), 7.96-7.90 (m, 1H), 7.57 (dd,J=11, 2 Hz, 1H), 7.41 (dd, J=8, 2 Hz, 1H), 7.13 (s, 1H), 7.02-6.97 (m,2H), 6.81 (d, J=8 Hz, 1H), 3.56 (s, 3H), 2.48 (q, J=8 Hz, 2H), 1.01 (t,J=8 Hz, 3H).

[2015]2-Ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (Step 5)

[2016] To a stirred solution of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(140 mg, 0.327 mmol) in CH₂Cl₂ (10 ml) was added triethylamine (40 mg,0.392 mmol), trifluoromethanesulfonic anhydride (100 mg, 0.358 mmol),and the mixture was stirred for 3 hours. The reaction mixture was pouredinto water. The whole was extracted with CH₂Cl₂. The organic layer waswashed with brine, dried over MgSO₄, and concentrated in vacuo. Thecompound was used for next reaction without purification.

[2017]4-[2-Ethyl-4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl]-1,3-thiazole(Step 6)

[2018] To a stirred solution of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (183 mg, 0.33 mmol) in dioxane (5 ml) wasadded 4-(tributylstannyl)thiazole (135 mg, 0.36 mmol),tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol), lithiumchloride (35 mg, 0.82 mmol), and the mixture was heated at refluxtemperature for 16 hours. The reaction mixture was cooled down to roomtemperature, and diluted with ethyl acetate. The whole was washed withsaturated potassium fluoride aqueous solution, and the precipitate wasremoved by filteration through celite. The resulting solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography eluting with ethyl acetate-hexane (1:2) to givetitle compound (25 mg, 15% yield).

[2019] mp: not detected.

[2020]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.96-7.90 (m, 1H), 7.55(d, J=8 Hz, 1H), 7.45 (d, J=12 Hz, 1H), 7.40 (d, J=2 Hz, 1H), 7.29-7.23(m, 2H), 7.13 (d, J=8 Hz, 1H), 6.84 (s, 1H), 3.23 (s, 3H), 2.79 (q, J=8Hz, 2H), 1.08 (t; J=8 Hz, 3H).

[2021] Anal. Calcd. for C₂₂H₁₇F₄N₃O₂S₂ {fraction (1/10)} Hexane: C,53.84; H. 3.68; N, 8.33. Found: C, 53.82; H, 3.92; N, 8.00.

Example 178

[2022]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-[3-methyl-4-(4-thiazolyl)phenyl]-4-trifluoromethyl-1H-imidazole

[2023]N-[3-Fluoro-4-(methylsulfonyl)phenyl]-4-bromo-3-methylbenzenecarboximidamide.(Step 1)

[2024] The subtitle compound was prepared according to the procedure ofExample 153 (step 1) using 4-bromo-3-methylbenzonitrile, instead of4-bromobenzonitrile.

[2025]2-(4-Bromo-3-methylphenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole.(Step 2)

[2026] The subtitle compound was prepared according to the procedure ofExample 153 (step 2) usingN-[3-fluoro-4-(methylsulfonyl)phenyl]-4-bromo-3-methylbenzenecarboximidamideinstead ofN-[3-fluoro-4-(methylsulfonyl)phenyl)-4-bromobenzenecarboximidamide.

[2027]¹H-NMR (DMSO-d₆) δ: 7.69-7.60 (m, 3H), 7.49 (s, 1H), 7.19-7.08 (m,2H), 6.71 (dd, J=2, 9 Hz, 1H), 4.51 (d, J=12 Hz, 1H), 3.99 (d, J=12 Hz,1H), 3.27 (s, 3H), 2.38 (s, 3H).

[2028]2-(4-Bromo-3-methylphenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.(Step 3)

[2029] The subtitle compound was prepared according to the procedure ofExample-153 (step 3) using2-(4-bromo-3-methylphenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazoleinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole.

[2030]¹H-NMR (CDCl₃) δ: 8.06 (dd, J=8, 8 Hz, 1H), 7.53-7.49 (m, 2H),7.46 (d, J=8 Hz, 1H), 7.24-7.15 (m, 2H), 6.82 (dd, J=2, 8 Hz, 1H), 3.28(s, 3H), 2.39 (s, 3H).

[2031]1-[3-Fluoro-4-(methylsulfonyl)phenyl]-2-[3-methyl-4-(4-thiazolyl)phenyl]4-trifluoromethyl-1H-imidazole.(Step 4)

[2032] The title compound was prepared according to the procedure ofExample 153 (step 4) using2-(4-bromo-3-methylphenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazoleinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.

[2033] mp: 197.0-198.0° C.

[2034]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.06 (dd, J=8, 8 Hz, 1H),7.59-7.53 (m, 3H), 7.41 (d, J=2 Hz, 1H), 7.29-7.19 (m, 2H), 7.05 (dd,J=2, 8 Hz, 1H), 3.28 (s, 3H), 2.46 (s, 3H).

[2035] Anal. Calcd. for. C₂₁H₁₅F₄N₃O₂S₂, 0.1hexane, 0.5H₂O: C, 51.79; H,3.45; N, 8.47. Found: C, 51.66; H, 3.30; N, 8.12.

[2036] mS (EI): m/z 481 (M⁺)

Example 179

[2037]2-Fluoro-4-[4-methyl-2-[4-(4-thiazolyl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide

[2038]4-[2-(4-Bromophenyl)-4-hydroxy-4-methyl-4,5-dihydro-1H-imidazol-1-yl]-2-fluorobenzenesulfonamide.(Step 1)

[2039] The subtitle compound was prepared according to the procedure ofExample 154 (step 2) using bromoacetone instead of3-bromo-1,1,1-trifluoroacetone.

[2040]4-[2-(4-Bromophenyl)-4-hydroxy-4-methyl-1H-imidazol-1-yl]-2-fluorobenzenesulfonamide. (Step 2)

[2041] The subtitle compound was prepared according to the procedure ofExample 153 (step 3) using4-[2-(4-bromophenyl)-4-hydroxy-4-methyl-4,5-dihydro-1H-imidazol-1-yl]-2-fluorobenzenesulfonamideinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]4-hydroxy-4-trifluoromethyl-4,5-dihydro-1H-imidazole.

[2042]¹H-NMR (CDCl₃) δ: 7.92 (dd, J=8, 8 Hz, 1H), 7.45 (d, J=9 Hz, 2H),7.23 (d, J=9 Hz, 2H), 7.09 (s, 1H), 7.06-7.04 (m, 1H), 6.91 (d, J=1 Hz,1H), 5.33 (brs, 2H), 2.05 (s, 3H).

[2043]2-Fluoro-4-[4-methyl-2-[4-(2-trimethylsilylthiazol-4-yl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide.(Step 3)

[2044] The title compound was prepared according to the procedure ofExample 153 (step 4) using4-[2-(4-bromophenyl)-4-hydroxy-4-methyl-1H-imidazol-1-yl]-2-fluorobenzenesulfonamideinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazoleand using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of4-(tributylstannyl)thiazole.

[2045] The crude product was used next reaction without furtherpurification.

[2046] mS (EI): m/z 486 (M⁺)

[2047]2-Fluoro-4-[4-methyl-2-[4-(4-thiazolyl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide.(Step 4)

[2048] To a stirred solution of2-fluoro-4-[4-methyl-2-[4-(2-trimethylsilylthiazol-4-yl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide(crude, 0.634 mmol) in THF (3 mL) was added tetrabutylammonium fluoride(0.95 mL, 1.0 M solution in THF, 0.95 mmol) at 0° C. The reactionmixture was warmed to room temperature and stirred for 30 minutes. Thereaction mixture was added water (20 mL) and extracted with ethylacetate (20 mL×3). The organic layer was washed with water and brine.After dried over MgSO₄ and concentration in vacuo. The crude mixture waspurified by flash chromatography eluting with hexane/ethyl acetate(1/3). The resulting solid was recrystallized from ethyl acetate-hexaneto give the title compound (0.116 g, 44.1% yield, via 2 steps).

[2049] mp: 145.0-147.0° C.

[2050]¹H-NMR (CDCl₃) δ: 8.87 (d, J=2 Hz, 1H), 8.00-7.94 (m, 1H), 7.89(d, J=8 Hz, 2H), 7.58 (d, J=2 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.13-7.07(m, 2H), 6.92 (s, 1H), 5.30 (brs, 2H), 2.34 (s, 3H).

[2051] Anal. Calcd. for. C_(19l H) ₁₅FN₄O₂S₂, 0.5H₂O: C, 53.89; H, 3.81;N, 13.23. Found: C, 53.66; H, 3.93; N, 12.88.

[2052] mS (EI): m/z 414 (M⁺)

Example 180

[2053]5-[3-Chloro-5-methyl-4-(4-thiazolyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[2054] 1-(4-[tert-Butyl(dimethyl)silyl]oxy]-3-methylphenyl-1-ethanone(Step 1)

[2055] The subtitle compound was prepared according to the procedure ofExample 177 (step 2) using 4′-hydroxy-3′-methylacetophenone instead of1-(3-ethyl-4-hydroxyphenyl)-1-ethanone.

[2056]¹H-NMR (CDCl₃) δ: 7.69 (d, J=2 Hz, 1H), 7.62 (dd, J=2, 8 Hz, 1H),6.70 (d, J=8 Hz, 1H), 2.45 (s, 3H), 2.15 (s, 3H), 0.93 (s, 9H), 0.16 (s,6H).

[2057]1-(4-[[tert-Butyl(dimethyl)silyl]oxy]-3-methylphenyl)-4,4,4-trifluoro-1,3-butanedione(Step 2)

[2058] The subtitle compound was prepared according to the procedure ofExample 177 (step 3) using1-(4-][tert-butyl(dimethyl)silyl]oxy]-3-methylphenyl)-1-ethanone insteadof 1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone.

[2059] mS (EI): m/z 360 (M⁺)

[2060]2-Methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(Step 3)

[2061] The subtitle compound was prepared according to the procedure ofExample 177 (step 4) using1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylphenyl)-4,4,4-trifluoro-1,3-butanedioneinstead of1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-4,4,4-trifluoro-1,3-butanedione.

[2062]¹H-NMR (CDCl₃) δ: 7.90 (dd, J=8, 8 Hz, 1H), 7.41 (dd. J=2, 11 Hz,1H), 7.23 (dd, J=2, 9 Hz, 1H), 7.09 (d, J=2 Hz, 1H), 6.88 (dd, J=2, 8Hz, 1H), 6.78 (d, J=8 Hz, 1H), 6.70 (s, 1H), 5.46 (brs, 1H), 3.24 (s,3H), 2.25 (s, 3H).

[2063]2-Chloro-6-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(Step 4)

[2064] To a stirred solution of2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(0.332 g, 0.8 mmol) in CH₂Cl₂ (10 ml) was added sulfuryl chloride (0.113g, 0.84 mmol) at room temperature, and the mixture was stirred for 30minutes. The reaction mixture was poured into water, and the whole wasextracted with CH₂Cl₂. The organic layer was washed with brine, driedover MgSO₄, and concentrated in vacuo. The residue was recystallizedwith CH₂Cl₂-hexane to give the subtitle compound (0.318 g, 88.6% yield).

[2065]¹H-NMR (CDCl₃) d: 7.93 (dd, J=8, 8 Hz, 1H), 7.44 (dd, J=2, 10 Hz,1H), 7.21 (dd, J=2, 9 Hz, 1H), 7.09 (d, J=2 Hz, 1H), 6.94 (s, 1H), 6.71(s, 1H), 5.86 (s, 1H), 3.24 (s, 3H), 2.27 (s, 3H).

[2066]2-Chloro-6-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (Step 5)

[2067] The subtitle compound was prepared according to the procedure ofExample 177 (step 5) using2-chloro-6-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenolinstead of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol.

[2068]¹H-NMR (CDCl₃) d: 7.97 (dd, J=8, 8 Hz, 1H). 7.46 (dd, J=2, 10 Hz,1H), 7.29 (d, J=2 Hz, 1H), 7.18 (dd, J=2, 8 Hz, 1H), 7.12 (d. J=2 Hz,1H), 6.83 (s, 1H), 3.25 (s, 3H), 2.44 (s, 3H).

[2069] mS (EI): m/z 580 (M⁺)

[2070]5-[3-Chloro-5-methyl-4-(4-thiazolyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole.(Step 6)

[2071] The subtitle compound was prepared according to the procedure ofExample 177 (step 6) using2-chloro-6-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate instead of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate.

[2072]¹H-NMR (CDCl₃) d: 8.97 (d, J=2 Hz, 1H), 7.98 (dd, J=8, 8 Hz, 1H),7.50 (d, J=10 Hz, 1H), 7.40 (d, J=2 Hz, 1H), 7.28-7.25 (m, 2H), 7.09 (s,1H), 6.83 (s, 1H), 3.25 (s, 3H), 2.14 (s, 3H).

[2073] Anal. Calcd. for. C₂₁H₁₄ClF₄N₃O₂S₂: C, 48.89; H, 2.74; N, 8.14.Found: C, 48.95; H, 2.86; N, 7.77.

[2074] mS (EI): m/z 515 (M⁺)

Example 181

[2075]4-Chloro-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[3-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[2076]2-Methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (Step 1)

[2077] The subtitle compound was prepared according to the procedure ofExample 177 (step 5) using2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenolinstead of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol.

[2078]¹H-NMR (CDCl₃) d: 7.94 (dd, J=7, 8 Hz, 1H), 7.41 (dd, J=2, 10 Hz,1H), 7.33-7.29 m, 2H), 7.18 (dd, J=1, 8 Hz, 1H), 7.11 (dd, J=2, 9 Hz,1H), 6.81 (s, 1H), 3.24 (s, 3H), 2.41 (s, 3H).

[2079] mS (EI): m/z 546 (M⁺)

[2080]2-Methyl-4-[4-chloro-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (Step 2)

[2081] To a stirred solution of2-methyl-4-[f-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (0.185 g, 0.339 mmol) in DMF (2 mL) was addedN-chlorosuccinimide (0.227 g, 1.70 mmol) at 0° C. The reaction mixturewas warmed to room temperature and stirred for 72 hours. The reactionmixture was added water (20 mL) and extracted with ethylacetate/hexane/ether=2/1/1 (20 mL×2). The organic layer was washed withwater and brine. After dried over MgSO₄ and concentration in vacuo. Thecrude mixture was purified by flash chromatography eluting withhexane/ethyl acetate (4/1) to give the subtitle compound (0.117 g, 59.7%yield).

[2082]¹H-NMR (CDCl₃) d: 7.92 (dd, J=8, 9 Hz, 1H), 7.40-7.32 (m, 3H),7.19-7.08 (m, 2H), 3.23 (s, 3H), 2.43 (s, 3H).

[2083] mS (EI): m/z 580 (M⁺)

[2084]4-Chloro-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[3-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole.(Step 3)

[2085] The subtitle compound was prepared according to the procedure ofExample 177 (step 6) using2-methyl-4-[4-chloro-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate instead of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate.

[2086]¹H-NMR (CDCl₃) d: 8.93 (s, 1H), 7.91 (t, J=8 Hz, 1H), 7.73 (d, J=8Hz, 1H), 7.47-7.39 (m, 2H), 7.30-7.27 (m, 1H), 7.21-7.13 (m, 2H), 3.22(s, 3H), 2.50 (s, 3H).

[2087] Anal. Calcd. for. C₂₁H₁₄ClF₄N₃O₂S₂, 0.2hexane: C, 49.63; H, 3.06;N, 7.96. Found: C, 49.99; H, 3.18; N, 7.82.

[2088] mS (EI): m/z 515 (M⁺)

Example 182

[2089]4-[4-(Methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone

[2090] The title compound was prepared according to the procedure ofExample 151 using3-(4-bromophenyl)-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone (WO9500501) instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[2091] mp: 236.8° C.

[2092]¹H-NMR (CDCl₃) δ: 9.22 (d, J=2.0 Hz, 1H), 8.25 (d, J=1.8 Hz, 1H),8.05 (d, J=8.6 Hz, 2H), 7.97 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H),7.43 (d, J=8.7 Hz, 2H), 5.44 (s, 2H), 3.25 (s, 3H).

[2093] Anal. Calcd. for C₂₀H₁₅NO₄S₂: C, 60.44; H, 3.80; N, 3.52. Found:C, 59.52; H, 3.96; N, 3.30.

Example 183

[2094]4-[5-Oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-franyl]benzenesulfonamideStep 1

[2095]4-[4-(4-Bromophenyl)-5-oxo-2,5-dihydro-3-franyl]benzenesulfonamide.

[2096] The title compound was prepared according to the procedure ofExample 32 using 4-(bromoacetyl)benzensulfonamide (GB 1071180) insteadof 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone, 4-bromophenylaceticacid instead of 4-(3-thienyl)phenylacetic acid.

[2097]¹H-NMR (DMSO-d₆) δ: (CDCl3) δ: 7.93 (d, J=8.2 Hz, 1H), 7.53 (d,J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 6.23(brs, 2H), 5.18 (5, 2H)

[2098] Step 2

[2099]4-[5-Oxo-4-[4-(1,3-thiazol-4-yl)phenyl)-2,5-dihydro-3-franyl]benzenesulfonamide.

[2100] The title compound was prepared according to the procedure ofExample 151 susing4-[4-(4-Bromophenyl)-5-oxo-2,5-dihydro-3-franyl]benzenesulfonamide (fromstep 1) instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[2101] mp: amorphous

[2102]¹H-NMR (CDCl₃) δ: (DMSO-d₆) δ: 9.23 (d, J=1.8 Hz, 1H), 8.25 (d,J=1.8 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.60 (d,J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 5.42 (s, 2H).

[2103] Anal. Calcd. for C₁₉H₁₄N₂O₄S₂: C, 57.27; H, 3.54; N, 7.03. Found:C, 50.67; H, 3.73; N, 6.24.

Example 184

[2104]5,5-Dimethyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone

[2105] (Step 1)

[2106]5,5-Dimethyl-3-(3-methyl-4-methoxy)phenyl-4-[4-(methylsulfonyl)phenyl-2(5H)-furanone

[2107] The title compound was prepared according to the procedure ofExample 166 step 1 using 4-methoxy-3-methylphenylacetic acid instead of4-bromophenylacetic acid. ¹H-NMR (DMSO-d₆) δ: 8.01 (d, J=8.6 Hz, 2H),7.60 (d, J=8.6 Hz, 2H), 7.13 (d, J=2.1 Hz, 1H), 7.03 (dd, J=2.1, 8.6 Hz,1H), 6.83 (d, J=8.6 Hz, 1H), 3.73 (s, 3H), 3.27 (s, 3H), 2.02 (s, 3H),1.53 (s, 6H).

[2108] Step 2

[2109]5,5-Dimethyl-3-(3-methyl-4-hydroxy)phenyl-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone

[2110] To a solution of5,5-dimethyl-3-(3-methyl-4-methoxy)phenyl-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone(from step 1, 2.0 g, 5.2 mmol) in CH₂Cl₂ (50 mL), boron tribromide (1.0M solution in CH₂Cl₂, 26 mL, 26 mmol) was added slowly at −78° C. andthe mixture was sirred for 0.5 h at that temperature. The mixture wasstirred for further 2 h at 0° C. The mixture was poured into saturatedaqueous NaHCO₃ (80 mL) and extracted with CH₂Cl₂ (70 mL×2), dried overMgSO₄, and concentarted in vacuo gave the title compound (1.9 g, 100%)

[2111]¹H-NMR (CDCl₃) δ: 8.00 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H),7.23 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.98 (brs, 1H), 3.11 (s, 31), 2.14 (s, 3H), 1.59 (s, 6H).

[2112] Step 3

[2113]4-[5,5-Dimethyl-4-[4-(methylsulfonyl)phenyl]-2-oxo-2,5-dihydro-3-furanyl]-2-methylphenyltrifluoromethanesulfonate.

[2114] To a solution of5,5-dimethyl-3-(3-methyl-4-hydroxy)phenyl-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone(from step 2, 2.0 g, 5.3 mmol) and triethylamine (0.88 mL, 6.3 mmol) inCH₂Cl₂ (50 mL), trifluoromethanesulfonic anhydride (0.97 mL, 5.8 mmol)was added at room temperature and stirred for 1.5 h. The mixture waspoued into H₂O'and extacted with CH₂Cl₂ (50 mL×2), dried over MgSO₄, andconcentarted in vacuo gave the title compound (2.5 g, 95%)

[2115]¹H-NMR (CDCl₃) δ: 8.04 (d, J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H),7.09 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 3.12 (s, 3H), 2.30 (s, 3H),1.61 (s, 6H).

[2116] Step 4

[2117]5,5-Dimethyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone

[2118] The title compound was prepared according to the procedure ofExample 151 using4-[5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-2-oxo-2,5-dihydro-3-furanyl]-2-methylphenyltrifluoromethanesulfonate from step 3 instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[2119] mp: 180.3° C.

[2120]¹H-NMR (DMSO-d₆) δ: 9.18 (d, J=1.8 Hz, 1h), 8.02 (d, J=8.4 Hz,2H), 7.85 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.52 (d, J=7.9 Hz,1H), 7.29 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 3.27 (s, 3H), 2.33 (s, 3H),1.57 (s, 6H).

[2121] Anal. Calcd. for C₂₃H₂₁NO₄S₂: C, 62.85; H, 4.82, N, 3.19. Found:C, 62.58; H, 5.10; N, 3.22.

Example 185

[2122]2-Methyl-4-[4-(methylsulfonyl)phenyl]-5-14-(1,3-thiazol-4-yl)phenyl-1,3-thiazole

[2123] Step 1

[2124] 2-(4-Bromophenyl)-1-(4-methylthiophenyl)ethanone.

[2125] 4-Bromophenylacetic acid (10.8 g, 0.050 mol) was disolved inthionyl chloride (50 mL) and stirred for 30 min at 90° C. The mixturewas concentrated and the residual oil was disolved in carbon disulfide(100 mL) and thioanisole (12.5 g, 0.10 mol) was added and the mixturewas cooled to 0° C. and AlCl₃ (14.7 g, 0.11 mol) was added portionwise.The mixture was stirred at room temperature for 16 h. The resultant darkgreen suspension was poured into ice water (150 mL) and extracted withCH₂Cl₂ (150 mL×2), washed with aqueous saturated NaHCO₃ (50 mL), driedover MgSO₄, and concentarted in vacuo gave the solid. The solid wassuspended in ether and collected by filtration to give the titlecompound (8.4 g, 46%).

[2126]¹H-NMR (DMSO-d₆) δ: 7.96 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.4 Hz,2H), 7.38 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 4.35 (s, 2H), 2.54(s, 3H).

[2127] Step 2

[2128] 2-Bromo2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone.

[2129] To a stirred suspension of2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone from step 1 (8.4 g,0.024 mol) in acetic acid (130 mL), bromine (3.8 g, 0.024 mol) in 25%hydrogen bromide-acetic acid solution (50 mL) was added dropwise at roomtemperature. After stirring for 4 h at room temperature, concentratedgave the yellow solid. The solid was suspended in ether and collected byfiltration, washed with ether to give the title compound (7.5 g, 73%).

[2130] H¹-NMR (DMSO-d6) δ: 7.98 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.6 Hz,2H), 7.50 (d, J=8.6 Hz, 2H), 7.37 (d, J=8.7 Hz, 2H), 7.14 (s, 1H), 2.53(s, 3H)

[2131] Step 3

[2132] 5-(4-Bromophenyl)-2-methyl-4-[4-(methylthio)phenyl]-1,3-thiazole.

[2133] A mixture of2-bromo2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone (7.6 g, 0.018mol) and thioacetamide 1.4 g, 0.018 mol) in ethanol (150 mL) wasrefluxed for 1 day. The mixture was concentrated and the solid waspurified by flash chromatography eluting with CH₂Cl₂/hexane (2/1) togive title compound (3.8 g, 56%). ¹H-NMR (CDCl₃) δ: 7.44 (d, J=8.6 Hz,2H), 7.40 (d, J=8.7 Hz, H), 7.18 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz,2H), 2.74 (s, 3H), 2.48 (s, 3H).

[2134] Step 4

[2135]5-(4-Bromophenyl)-2-methyl-4-[4-(methylsulfonyl)phenyl]-1,3-thiazole.

[2136] To a solution of5-(4-bromophenyl)-2-methyl-4-[4-(methylthio)phenyl]-1,3-thiazole fromstep 3 (3.8 g, 0.010 mol) in CH₂Cl₂ (40 mL), m-CPBA (6.2 g, 0.025 mol)was added at 0° C. The mixture was allowed to warm to room temperratureand stirred for 12 hours. The mixture was poured into aqueous saturatedNa₂SO₃ (40 mL) and diluted with CH₂Cl₂ (50 mL). Organic later wasseparated and washed with aqueous saturated NaHCO₃ (50 mL), dried overMgSO₄, and concentarted in vacuo. The mixture was purified by flashchromatography eluting with ethyl acetate/hexane (1/1) to give titlecompound (3.1 g, 76%).

[2137]¹H-NMR (CDCl₃) δ: 7.85 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H),7.48 (d, J=8.4 Hz, H), 7.17 (d, J=8.4 Hz, 2H), 3.05 (s, 3H), 2.76 (s,3H).

[2138] Step 5

[2139]2-Methyl-4-[4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-thiazole.

[2140] The title compound was prepared according to the procedure ofExample 151 using5-(4-bromophenyl)-2-methyl-4-[4-(methylsulfonyl)phenyl]-1,3-thiazolefrom step 1 instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole.

[2141] mp: 193.9° C.

[2142]¹H-NMR (CDCl₃) δ: 8.90 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H),7.84 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.59 (d, J=1.6 Hz, 1H),7.38 (d, J=8.2 Hz, 2H), 3.04 (s, 3H), 2.78 (s, 3H).

[2143] Anal. Calcd. for C₂₀H₁₆N₂O₂S₃: C, 58.23; H, 3.91; N, 6.79. Found:C, 58.07; H, 3.99; N, 6.64.

Example 186

[2144]1-[4-(Methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[2145] 1-[4-(tert-Butyldimethylsilyl)oxy]-2-methylphenyl]ethanone (Step1)

[2146] To a stirred solution of 1-[4-Hydroxy-2-methylphenyl]ethanone (10g) in DMF (150 mL) was added imidazol (6.8 g) andtert-Butyldimethylsilyl chloride (12.04 g) the mixture was stirredcontinued for 3 hours. water (300 mL) was added to the reaction mixture.the whole was extracted with diethyl ether (200 mL×2). The combineddiethyl ether extracts was washed with saturated NaHCO₃ solution, driedover sodium sulfate, and concentrated in vacuo. The resulting oil wasdistilled under reduced pressuer (b.p.=120-123° C. at 0.8 mmHg) to givetitle compound (16.34 g).

[2147]¹H-NMR (CDCl₃) δ: 7.70-7.66 (m, 1H), 6.71-6.68 (m, 2H), 2.54 (s,3H), 2.53 (s, 3H), 0.99 (s, 9H), 0.23 (s, 6H).

[2148]1-[4-[(tert-Butyl(dimethylsilyl]oxy]-2-methylphenyl]-4,4,4-trifluoro-1,3-butadione(Step 2)

[2149] The title compound was prepared according to the procedure ofExample 27 (step 1) using1-[4-(tert-Butyl(dimethylsilyl)oxy)₂-methylphenyl]ethanone, instead of4-(2,5-dimethylpyrrol-1-yl)acetophenone.

[2150]¹H-NMR (CDCl₃) δ: 7.4 (br, 1H), 6.7-6.6 (br m, 2H), 2.32 (br, 3H),0.97 (s, 9H), 0.19 (s, 6H).

[2151] mS (EI): m/z 360 (M⁺), 303

[2152]3-Methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(Step 3)

[2153] [4-(methylsulfonyl)phenyl]hydrazine hydrochloride (0.37 g, 1.6mmol) was added to a solution of1-[4-[(tert-Butyl(dimethylsilyl]oxy]-2-methylphenyl]-4,4,4-trifluoro-1,3-butadione(0.6 g, 1.6 mmol) in EtOH (5 mL). The mixture was heated at refluxtemperature for 15 hours and cooled down to room temperature. Thereaction mixture was concentrated in vacuo, and the residue was taken upin ethyl acetate, washed with water and brine, dried over magnesiumsulfate, and concentrated in vacuo. The residue and tetrabutylammoniumfluoride (1.0M solution in THF; 2 mL) were added to THF (3 mL).Resulting mixture was stirred for 1 hour and taken up in ethyl acetate,washed with water and brine, dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with hexane/ethyl acetate (2/1) to give the title compound (0.56g, 58.0% yield).

[2154]¹H-NMR (CDCl₃) δ: 7.88 (dt, J=9, 2 Hz, 2H), 7.49 (dt, J=9, 2 Hz,2H), 7.09-7.05 (m, 1H), 6.73-6.70 (m, 2H), 6.67 (s, 1H), 3.05 (s, 3H).

[2155]3-Methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (Step 4)

[2156] To a stirred solution of3-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol(10.3 g, 0.76 mmol) in dichloromethane (5 ml) was added triethylamine(0.101 g, 11.0 mmol), trifluoromethanesulfonic anhydride (0.226 g, 0.8mmol), and the mixture was stirred for 2 hours. The reaction mixture waspoured into water. The whole was extracted with dichloromethane. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate-hexane (1:2) to give title compound (0.37 g).

[2157]¹H-NMR (CDCl₃) δ: 7.91 (dt, J=9, 2 Hz, 2H), 7.45 (dt, J=9, 2 Hz,2H), 7.36-7.32 (m, 1H), 7.23-7.19 (m, 2H), 6.65 (s, 1H), 3.05 (s, 3H),2.08 (s, 3H).

[2158]1]-4-(Methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole.(Step 5)

[2159] The title compound was prepared according to the procedure ofExample 177 (step 6) using3-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate, instead of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate.

[2160] mp: 174.7° C.

[2161]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 7.90-7.84 (m, 3H), 7.82(br d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.52 (dt, J=9, 2 Hz, 2H), 7.29(d, J=8 Hz, 1H), 6.75 (s, 1H), 3.04 (s, 3H), 2.08 (s, 3H).

[2162] Anal. Calcd. for: C₂₁H₁₆N₃O₂F₃S₂: C, 54.42; H, 3.48; N, 9.07.Found: C, 54.20; H, 3.60; N, 9.00.

Example 187

[2163]1-[3-Fluoro4-(methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole

[2164]4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methyl-phenyltrifluoromethanesulfonate (Step 1)

[2165] [3-Fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride (0.265g, 1.1 mmol) was added to a solution of1-[4-[(tert-Butyl(dimethylsilyl]oxy]-2-methylphenyl]-4,4,4-trifluoro-1,3-butadione(0.4 g, 1.1 mmol) in EtOH (5 mL). The mixture was heated at refluxtemperature for 15 hours and cooled down to room temperature. Thereaction mixture was concentrated in vacuo, and the residue was taken upin ethyl acetate, washed with water and brine, dried over magnesiumsulfate, and concentrated in vacuo. The residue and tetrabutylammoniumfluoride (1.0M solution in THF 2 mL) were added to THF (3 mL). Theresulting mixture was stirred for 1 hour and taken up in ethyl acetate,washed with water and brine, dried over magnesium sulfate, andconcentrated in vacuo. The residue was used for next reaction withoutpurification. To a stirred solution of the crude product in CH₂Cl₂ (5ml) was added triethylamine (0.202 g), trifluoromethanesulfonicanhydride (0.423 g), and the mixture was stirred for 3 hours. Thereaction mixture was poured into water. The whole was extracted withdichloromethane. The organic layer was washed with brine, dried overMgSO₄, and concentrated in vacuo. The residue was purified by flashchromatography eluting with ethyl acetate-hexane (1:2) to give titlecompound (0.4 g).

[2166]¹H-NMR (CDCl₃) δ: 7.78 (dd, J=9, 8 Hz. 1H), 7.25-7.13 (m, 4H),7.00 (dd, J=9, 1 Hz, 1H), 6.65 (s, 1H), 3.12 (s, 3H), 2.00 (s, 3H).

[2167]1-[3-Fluoro4-(methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole.(Step 2

[2168] The title compound was prepared according to the procedure ofExample 177 (step 6) using4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methyl-phenyltrifluoromethanesulfonate, instead of2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate.

[2169] mp: 131.9° C.

[2170]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.90 (br, 1H), 7.85 (dd,J=8, 2 Hz, 1H), 7.84 (dd, J=9, 8 Hz, 1H), 7.65 (d, J=2 Hz, 1H)+7.39 (dd,J=11, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (dd, J=9, 2 Hz, 1H), 6.75(s, 1H), 3.20 (s, 3H), 2.11 (s, 3H).

[2171] Anal. Calcd. for: C₂₁H₁₅N₃O₂F₄S₂: C, 52.39; H, 3.14; N, 8.73.Found: C, 52.56; H, 3.20; N, 8.68.

Example 188

[2172]2-Fluoro-4-[5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl]benzenesulfonamide

[2173] 1-(4-Bromo3-methylphenyl)-2-(3-fluorophenyl)ethanone. (Step 1)

[2174] The title compound was prepared according to the procedure ofstep 3 in the Example 169 using 3-fluorobenzyl bromide and4-bromo-3-methylbenzoyl chloride (Cignarella; G.; Curzu, M. M.; Grella,G.; Loriga, M.; Anania, V.; Desole, M. S.; J. Farmaco. Ed. Sci., 1983,38, 187-198.).

[2175]¹H-NMR (CDCl₃) δ: 7.85 (1H, br s), 7.68-7.60 (2H, m), 7.34-7.25(1H, m), 7.05-6.92 (3H, m), 4.24 (2H, s), 2.46 (3H, s).

[2176]3-(4-Bromo-3-methylphenyl)-4-(3-fluorophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.(Step 2)

[2177] The title compound was prepared according to the procedure ofstep 1 in the Example 168 using1-(4-bromo3-methylphenyl)-2-(3-fluorophenyl)ethanone, instead of1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone.

[2178]¹H-NMR (CDCl₃) δ: 7.55 (1H, d, J=1.8 Hz), 7.45 (1H, d, J=8.2 Hz),7.37-7.26 (1H, m), 7.19 (1H, dd, J=2.3 and 8.4 Hz). 7.05-6.81 (3H, m),4.46 (1H, s), 3.00 (1H, br s), 2.35 (3H, s), 1.30 (3H, s).

[2179] 3-(4-Bromop-3-methylhenyl)-4-(3-fluorophenyl)-5-methylisoxazole.(Step 3)

[2180] The title compound was prepared according to the procedure ofstep 2 in the Example 168 using3-(4-bromo3-methylphenyl)-4-(3-fluorophenyl)-5-methyl-4,5-dihydro-5-isoxazolol,instead of3′-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.

[2181]¹H-NMR (CDCl₃) δ: 7.45 (1H, d, J=8.2 Hz), 7.39 (1H, d, J=1.8 Hz),7.38-7.30 (1H, m), 7.10-6.86 (4H, m), 2.45 (3H, s), 2.34 (3H, s).

[2182]4-[3-(4-Bromo-3-methylphenyl)-5-methyl-4-isoxazolyl)-2-fluorobenzenesulfonamideand2-[3-(4-Bromophenyl)-5-methyl-4-isoxazolyl]4-fluorobenzenesulfonamide.(Step 4)

[2183] The title compounds were prepared according to the procedure ofstep 4 in the Example 172 using3-(4-bromo-3-methylphenyl)-4-(3-fluorophenyl)-5-methylisoxazole, insteadof 3-(4-bromophenyl)-4-(3-fluorophenyl)-5-methylisoxazole.

[2184] First, 42% of2-[3-(4-bromophenyl)-5-methyl-4-isoxazolyl]4-fluorobenzenesulfonamidewas obtained as a pale yellow foam.

[2185]¹H-NMR (CDCl₃) δ: 8.20 (1H, dd, J=5.8 and 8.7 Hz), 7.42 (1H, brs), 7.38 (1H, d, J=8.4 Hz), 7.31-7.22 (1H, m), 7.01 (1H, dd, J=2.1 and8.4 Hz), 6.93 (1H, dd, J=2.1 and 8.4 Hz), 4.89 (2H, br s), 2.30 (6H, s).

[2186] The second fractions gave 37% of4-[3-(4-bromo-3-methylphenyl)-5-methyl-4-isoxazolyl]-2-fluorobenzenesulfonamideas a colorless foam.

[2187]¹H-NMR (CDCl₃) δ: 7.91 (1H, t, J=8.2 Hz), 7.50 (1H, d, J=8.2 Hz),7.41 (1H, d, J=1.5 Hz), 7.09-7.01 (2H, m), 6.92 (1H, dd, J=2.1 and 8.6Hz), 5.16 (2H, br s), 2.50 (3H, s), 2.39 (3H, s).

[2188]2-Fluoro-4-[5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl]benzenesulfonamide.(Step 5)

[2189] The title compound was prepared according to the procedure ofstep 4 in the Example 168 using4-[3-(4-bromo-3-methylphenyl)-5-methyl-4-isoxazolyl]-2-fluorobenzenesulfonamide,instead of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[2190] m.p.: 114-116° C. (from ethyl acetate/diisopropyl ether/hexane)

[2191]¹H-NMR (CDCl₃) δ: 8.91 (1H, d, J=2.0 Hz), 7.92 (1H, dd, J=6.9 and8.1 Hz), 7.60 (1H, d, J=7.7 Hz), 7.47 (1H, br s), 7.40 (1H, d, J=1.8Hz), 7.17-7.05 (3H, m), 5.09 (2H, br s), 2.52 (3H, s), 2.45 (3H, s).

[2192] mS; 429 (M⁺).

Example 189

[2193]5-Methyl-3-[4-(methylsulfonyl)phenyl]-4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole

[2194] 2-(4-Bromophenyl)-]-(4-methylthiophenyl)ethanone. (Step 1)

[2195] The title compound was prepared according to the procedure ofstep 3 in the Example 169 using 4-bromobenzyl bromide and4-methylthiobenzoyl chloride.

[2196]¹H-NMR (CDCl₃) δ: 7.92-7.86 (2H, m), 7.47-7.41 (2H, m), 7.29-7.22(2H, m), 7.16-7.10 (2H, m), 4.19 (2H, s), 2.52 (3H, s).

[2197]4-(4-Bromophenyl)-3-(4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.(Step 2)

[2198] The title compound was prepared according to the procedure ofstep 1 in the Example 168 using2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone, instead of1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone.

[2199]¹H-NMR (CDCl₃) δ: 7.53-7.44 (4H, m), 7.19-7.00 (4H, m), 4.45 (1H,s), 2.45 (3H, s), 1.28 (3H, s). One signal due to OH group was notobserved.

[2200] 4-(4-Bromophenyl)-3-(4-methylthiophenyl)-5-methylisoxazole. (Step3)

[2201] The title compound was prepared according to the procedure ofstep 2 in the Example 168 using4-(4-bromophenyl)-3-(4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol,instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.

[2202]¹H-NMR (CDCl₃) δ: 7.54-7.48 (2H, m), 7.35-7.30 (2H, m), 7.21-7.16(2H, m), 7.08-7.02 (2H, m), 2.48 (3H, s), 2.43 (3H, s).

[2203] 4-(4-Bromophenyl)-5-methyl-3-(4-methylsulfonylphenyl)isoxazole.(Step 4)

[2204] The title compounds were prepared according to the procedure ofstep 3 in the Example 168 using4-(4-bromophenyl)-3-(4-methylthiophenyl)-5-methylisoxazole, instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole.

[2205]¹H-NMR (CDCl₃) δ: 7.96-7.90 (2H, m), 7.66-7.60 (2H, m), 7.58-7.52(2H, m), 7.17-7.11 (2H, m), 3.07 (3H, s), 2.47 (3H, s).

[2206]2-Fluoro-4-[5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl]benzenesulfonamide.(Step 5)

[2207] A mixture of4-(4-bromophenyl)-5-methyl-3-(4-methylsulfonylphenyl)isoxazole (300 mg,0.765 mmol) and tributyl(2-trimethylsilylthiazol-4-yl)tin in toluene (5ml) in the presence of tetrakis(triphenylphosphine)palladium (88 mg,0.0765 mmol) was refluxed for 17 hours. After filtration through a padof Celite, the filtrate was concentrated to give a black oil. This wasdissolved in tetrahydrofuran (8 ml) and 2M hydrochloric acid (4 ml) wasadded there at room ttemperature. The mixture was stirred for 1 hour atthe same temperature, diluted with ethyl acetate (150 ml), washed withwater (50 ml) and saturated aqueous sodium bicarbonate (50 ml×2), anddried over anhydrous magnesium sulfate. Removal of solvent gave a yellowresidue, which was chromatographed on a column of silica gel (60 g) aseluting with ethyl acetate/hexane (1:2) to afford 158 mg (52%) of thetitle compound as a white solid.

[2208] m.p.: 159° C. (from ethyl acetate/diisopropyl ether/hexane)

[2209]¹H-NMR (CDCl₃) δ: 8.91 (1H, d, J=1.8 Hz), 8.01-7.87 (4H, m),7.72-7.66 (2H, m), 7.61 (1H, d, J=2.0 Hz), 7.29-7.22 (2H, m), 3.06 (3H,s), 2.52 (3H, s).

[2210] mS; 396 (M⁺).

Example 190

[2211]4-[3-Methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazoyl]benzenesulfonamide

[2212] 4-(4-Bromophenyl)-3-phenyl-3-buten-2-one. (step 1)

[2213] A mixture of phenylacetone (4.92 g, 36.7 mmol) and4-bromobenzaldehyde (6.78 g, 36.7 mmol) in benzene (40 ml) in thepresence of piperidine (0.11 ml, 1.47 mmol) was refluxed for 48 hours.After evaporation, the obtained residue was chromatographed on a columnof silica gel (300 g) as eluting with ethyl acetate/hexane (1:20 to 1:2)to afford a yellow solid, which was washed with ethyl acetate/hexane togive 4.22 g (38%) of the title compound as a pale yellow solid.

[2214]¹H-NMR (CDCl₃) δ: 7.56 (1H, s), 7.46-7.37 (3H, m), 7.32-7.26 (2H,m), 7.19-7.12 (2H, m), 6.92-6.86 (2H, m), 2.29 (3H, s).

[2215] 4-(4-Bromophenyl)-3-phenyl-3-buten-2-one oxime. (Step 2)

[2216] A mixture of 4-(4-bromophenyl)-3-phenyl-3-buten-2-one (2.00 g,6.64 mmol), hydroxylamine hydrochloride (923 mg, 13.3 mmol) and sodiumacetate (1.09 g, 13.3 mmol) in ethanol was-refluxed for 2 hours. Afterevaporation, the residue was diluted with diethyl ether (200 ml), washedwith water (50 ml), 2M hydrochloric acid (50 ml), and saturated aqueoussodium bicarbonate (50 ml×2), and dried over anhydrous magnesiumsulfate. Removal of solvent gave 2.06 g (98%) of the title compounds.TLC: Rf=0.26 and 0.15 (ethyl acetate/hexane=1/5).

[2217] 5-(4-Bromophenyl)-3-methyl-4-phenylisoxazole. (Step 3)

[2218] To a stirred mixture of 4-(4-bromophenyl)-3-phenyl-3-buten-2-oneoxime (2.06 g, 6.52 mmol) and sodium bicarbonate (2.46 g, 29.3 mmol) ina mixture of tetrahydrofuran (30 ml) and water (20 ml) was added asolution of potassium iodide (4.09 g, 24.7 mmol) and iodine (1.98 g,7.82 mmol) in water (30 ml) at room temperature. Then, the resultingmixture was refluxed for 5 hours in the dark. After cooling down to roomtemperature, 50 ml of saturated aqueous sodium sulfite was added. Theorganic layer was separated and the water layer was extracted, withethyl acetate (100 ml×2). The combined organic layers were dried overanhydrous magnesium sulfate and evaporated. The obtained residue waschromatographed on a column of silica gel (120 g) as eluting with ethylacetate/hexane (1:15) to afford 1.64 g (80%) of the title compound as apale brown oil.

[2219]¹H-NMR (CDCl₃) δ: 7.49-7.37 (7H, m), 7.30-7.26 (2H, m), 2.24 (3H,s).

[2220] 4-[5-(4-Bromophenyl)-3-methyl-4-isoxazolyl]benzenesulfonamide.(Step 4)

[2221] To stirred chlorosulfonic acid (5 ml) was added5-(4-bromophenyl)-3-methyl-4-phenylisoxazole (628 mg, 2.00 mmol) at −78°C. The mixture was allowed to warm up to room temperature and stirredfor 1 hour. The resulting black mixture was poured into ice-conc.ammonia water (200 ml) carefully and extracted with ethyl acetate (150ml). The separated organic layer was, washed with water (50 ml×2), driedover anhydrous sodium sulfate, and evaporated. The obtained residue waschromatographed on a column of silica gel (60 g) as eluting with ethylacetate/hexane (1/1) to afford 512 mg (87%) of the title compound as apale brown solid.

[2222]¹H-NMR (CDCl₃) δ: 7.82-7.76 (2H, m), 7.59-7.53 (2H, m), 7.50-7.44(2H, m), 7.36 (2 H, br s), 7.32-7.26 (2H, m), 2.11 (3H, s).

[2223]4-[3-Methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl]benzenesulfonamide.(Step 5)

[2224] The title compound was prepared according to the procedure ofstep 4 in the Example 168 using4-[5-(4-bromophenyl)-3-methyl-4-isoxazolyl]benzenesulfonamide, insteadof3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[2225] m.p.: 236° C. (from ethyl acetate)

[2226]¹H-NMR (DMSO-d₆) δ: 9.10 (1H, d, J=2.0 Hz), 8.16 (1H, d, J=2.0Hz), 7.95 (2H, d, J=8.6 Hz), 7.81 (2H, d, J=8.6 Hz), 7.51 (2H, d, J=8.6Hz), 7.43 (2H, d, J=8.7 Hz), 7.36 (2H, br s), 2.12 (3H, s).

[2227] mS; 397 (M⁺).

Example 191

[2228]3-Methyl-5-[4-(methylsulfonyl)phenyl]-4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole

[2229] 3-(4-Bromophenyl)-4-(4-methylthiophenyl)-3-buten-2-one. (Step 1)

[2230] The title compound was prepared according to the procedure ofstep 1 in the Example 190 using (4-bromophenyl)acetone and4-methylthiobenzaldehyde; instead of phenylacetone and4-bromobenzaldehyde.

[2231]¹H-NMR (CDCl₃) δ: 7.60 (1H, s), 7.58-7.52 (2H, m), 7.08-7.01 (4H,m), 6.98-6.92 (2H, m), 2.44 (3H, s), 2.34 (3H, s).

[2232] 3-(4-Bromophenyl-4-(4-methylthiophenyl)-3-buten-2-one oxime.(Step 2)

[2233] The title compound was prepared according to the procedure ofstep 2 in the Example 190 using3-(4-bromophenyl)-4-(4-methylthiophenyl)-3-buten-2-one, instead of4-(4-bromophenyl)-3-phenyl-3-buten-2-one.

[2234] TLC: Rf=0.12 (ethyl acetate/hexane=1/5).

[2235] 4-(4-Bromophenyl)-3-methyl-5-(4-methylthiophenyl)isoxazole. (Step3)

[2236] The title compound was prepared according to the procedure ofstep 3 in the Example 190 using3-(4-bromophenyl)-4-(4-methylthiophenyl)-3-buten-2-one oxime, instead of4-(4-bromophenyl)-3-phenyl-3-buten-2-one oxime.

[2237]¹H-NMR (CDCl₃) δ: 7.57 (2H, d, J=8.2 Hz), 7.42 (2H, d, J=8.4 Hz),7.17 (2H, d, J=8.9 Hz), 7.16 (2H, d, J=8.2 Hz), 2.48 (3H, s), 2.23 (3H,s).

[2238] 4-(4-Bromophenyl)-3-methyl-5-[4-(methylsulfonyl)phenyl]isoxazole.(Step 4)

[2239] The title compound was prepared according to the procedure ofstep 3 in the Example 168 using4-(4-bromophenyl)-3-methyl-5-(4-methylthiophenyl)isoxazole, instead of3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methylisoxazole.

[2240]¹H-NMR (CDCl₃) δ: 7.95-7.89 (2H, m), 7.74-7.69 (2H, m), 7.65-7.58(2H, m), 7.19-7.14 (2H, m), 3.06 (3H, s), 2.26 (3H, s).

[2241]3-Methyl-5-[4-(methylsulfonyl)phenyl]-4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole.(Step 5)

[2242] The title compound was prepared according to the procedure ofstep 4 in the Example 168 using4-(4-bromophenyl)-3-methyl-5-[4-(methylsulfonyl)phenyl]isoxazole,instead of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[2243] m.p.: 119° C. (from ethyl acetate/hexane)

[2244]¹H-NMR (CDCl3) δ: 8.93 (1H, d, J=2.0 Hz), 8.05 (2H, br d, J=7.9Hz), 7.90 (2H, br d, J=8.1 Hz), 7.77 (2H, br d, J=8.0 Hz), 7.65 (1H, d,J=2.0 Hz), 7.37 (2H, br d, J=7.9 Hz), 3.05 (3H, s), 2.30 (3H, s).

[2245] mS; 396 (M⁺).

Example 192

[2246]2-Fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide

[2247] 2-Acetoxy-1-(4-bromophenyl)-2-(3-fluorophenyl)-1-ethanone. (Step1)

[2248] The title compound was prepared according to the procedure ofExample 169 (step 5) using1-(4-bromophenyl)-2-(3-fluorophenyl)-1-ethanone, instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone.

[2249]¹H-NMR (CDCl₃) δ 7.78 (d, J=8.9 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H),7.31-7.39 (m, 1H), 7.14-7.23 (m, 2H), 7.01-7.09 (m, 1H), 6.76 (s, 1H),2.21 (s, 3H)

[2250] 4-(4-Bromophenyl)-5-(3-fluorophenyl)-2-methyl-1,3-oxazole. (Step2).

[2251] The title compound was prepared according to the procedure ofExample 169 step 6 using2-acetoxy-1-(4-bromophenyl)-2-(3-fluorophenyl)-1-ethanone, instead of2-acetoxy-1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone.

[2252]¹H-NMR (CDCl₃) δ 7.51 (s, 4H), 7.24-7.34 (m, 3H), 6.98-7.06 (m,1H), 2.55 (s, 3H).

[2253]4-[4-(4-Bromophenyl)-2-methyl-1,3-oxazol-5-yl]-2-fluorobenzenesulfonamide.(Step 3)

[2254] The title compound was prepared according to the procedure ofExample 172 (step 4) using4-(4-bromophenyl)-5-(3-fluorophenyl)-2-methyl-1,3-oxazole, instead of3-(4-bromophenyl)-5-methyl-4-phenylisoxazole.

[2255]¹H-NMR (CDCl₃) δ 7.87 (t, J=7.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H),7.40-7.49 (m, 4H), 5.11 (br s, 2H), 2.58 (s, 3H).

[2256]2-Fluoro-4-[2-methyl-4-[4-(1,3-thiazol-4-yl)phenyl-1,3-oxazol-5-yl]benzenesulfonamide.(Step 4)

[2257] The title compound was prepared according to the procedure ofExample 168 (step 4) using4-[4-(4-bromophenyl)-2-methyl-1,3-oxazol-5-yl]-2-fluorobenzenesulfonamideinstead of3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole.

[2258] mp: 116-118° C.

[2259]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H),7.86 (t, J=7.7 Hz, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.62 (d, J=1.8 Hz),7.45-7.54 (m, 2H), 5.12 (br s, 2H), 2.60 (s, 3H).

[2260] Anal. Calcd. for C₁₉H₁₄N₃O₃F₁S₂.0.7EtOH: C, 54.73; H, 4.10; N,9.39. Found: C, 54.46; H, 4.42; N, 9.09.

Example 193

[2261]2-fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide

[2262] 2-(4-Bromophenyl)-1-(3-fluorophenyl)-1-ethanone. (Step 1)

[2263] The title compound was prepared according to the procedure ofExample 169 step 3 using 3-fluorobenzoyl chloride and4-bromobenzylbromide, instead of 4-bromobenzoyl chloride and4-(bromomethyl)-2-fluoro-1-(methylsulfanyl)benzene.

[2264]¹H-NMR (CDCl₃) δ 7.82 (dt, J=1.5, 7.6 Hz, 1H), 7.64-7.69 (m, 1H),7.26-7.32 (m, 1H), 7.44-7.50 (m, 3H), 7.13 (d, J=8.2 Hz, 2H), 4.22 (s,2H).

[2265] 2-Acetoxy-1-(4-bromophenyl)-2-(3-fluorophenyl)-1-ethanone. (Step2)

[2266] The title compound was prepared according to the procedure ofExample 169 step 5 using2-(4-bromophenyl)-1-(3-fluorophenyl)-1-ethanone, instead of1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone.

[2267]¹H-NMR (CDCl₃) δ 7.68 (d, J=7.7 Hz, 1H), 7.57-7.62 (m, 1H), 1.51(d, J=8.4 Hz, 2H), 7.20-7.44 (m, 4H), 6.73 (s, 1H), 2.20 (s, 3H).

[2268] 5-(4-Bromophenyl)-4-(3-fluorophenyl)-2-methyl-1,3-oxazole. (Step3).

[2269] The title compound was prepared according to the procedure ofExample 169 step 6 using2-acetoxy-1-(4-bromophenyl)-2-(3-fluorophenyl)-1-ethanone, instead of2-acetoxy-1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone.

[2270]¹H-NMR (CDCl₃) δ 7.26-7.52 (m, 7H), 7.02-7.06 (in, 1H), 2.54 (s,3H).

[2271]4-[5-(4-Bromophenyl)-2-methyl-1,3-oxazol-4-yl]-2-fluorobenzenesulfonamide.(Step 4)

[2272] The title compound was prepared according to the procedure ofExample 172 step 4 using5-(4-bromophenyl)-4-(3-fluorophenyl)-2-methyl-1,3-oxazole, instead of3-(4-bromophenyl)-5-methyl-4-phenylisoxazole.

[2273]¹H-NMR (CDCl₃) δ 7.87 (t, J=7.6 Hz, 1H), 7.55 (t, J=8.6 Hz, 4H),7.42 (d, J=8.6 Hz, 2H), 5.07 (br s, 2H), 2.56 (s, 3H).

[2274]2-Fluoro-4-[2-methyl-5-[4-(2-trimethylsilyl-1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide.(Step 5)

[2275] The title compound was prepared according to the procedure ofExample 153 (step 4) using4-[5-(4-Bromophenyl)-2-methyl-1,3-oxazol-4-yl]-2-fluorobenzenesulfonamideinstead of2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazoleand using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of4-(tributylstannyl)thiazole.

[2276] The crude product was used next reaction without furtherpurification.

[2277]2-Fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide.(Step 6).

[2278] The title compound was prepared according to the procedure ofExample 179 (step 4) using2-fluoro-4-[2-methyl-5-[4-(2-trimethylsilyl-1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamideinstead of2-fluoro-4-[4-methyl-2-[4-(2-trimethylsilylthiazol-4-yl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide.

[2279] mp: 192-194° C.

[2280]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H),7.87 (t, J=8.4 Hz, 1H), 7.57-7.66 (m, 5H), 5.07 (br s, 2H), 2.58 (s,3H).

[2281] Anal. Calcd. for C₁₉H₁₄N₃O₃F₁S₂.0.2H₂O.0.4AcOEt: C, 54.46; H,3.90; N, 9.25. Found: C, 54.27; H, 4.02; N, 9.03.

Example 194

[2282]4-[4-[3-(Difluoromethyl)-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl]-2-methylphenyl]-1,3-thiazole

[2283]4,4-Diifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 1)

[2284] The title compound was prepared according to the procedure ofExample 106 step 5) using ethyl difluoroacetate instead of ethyltrifluoroacetate.

[2285]¹H-NMR (CDCl₃) δ: 8.96 (d, J=2 Hz, 1H), 7.88-7.75 (m, 3H), 7.48(d, J=2 Hz, 1H), 6.60 (s, 1H), 6.02 (t, J=54 Hz, 1H), 2.55 (s, 3H).

[2286]4-[4-[3-(Difluoromethyl)-1-[3-Fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl]-2-methylphenyl-1,3-thiazole(Step 2)

[2287] The title compound was prepared according to the procedure ofExample 106 (step 6) using4,4-Difluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of4,4,4-trifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3]-butanedione.

[2288] mp: 122.9° C.

[2289]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.91 (dd, J=9, 7 Hz, 1H),7.65 (d, J=8 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 7.43 (dd, J=11, 2 Hz, 1H),7.28-7.24 (m, 2H), 7.09 (brd, J=8 Hz, 1H), 6.78 (s, 1H), 6.77 (t, J=55Hz 1H), 3.23 (s, 3H), 2.47 (s, 3H).

[2290] Anal. Calcd. for C₂₁H₁₆F₃N₃O₂S₂: C, 54.42; H, 3.48; N, 9.07.Found: C, 54.27; H, 3.57; N, 8.99.

Example 195

[2291]3-(Difluoromethyl)-2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1H-pyrazol-1-yl]benzenesulfonamide

[2292] The title compound was prepared according to the procedure ofExample 106 (step 6) using4,4-Diifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(example 194, step 1) instead of4,4,4-trifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneand (2-fluoro-4-sulfamoylphenyl)hydrazine hydrochloride instead of(2-fluoro-4-methylsulfonylphenyl)hydrazine hydrochloride.

[2293] mp: 204.3° C.

[2294]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz. 1H), 7.86 (dd, J=8, 8 Hz, 1H),7.64 (d, J=8 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 7.39 (dd, J=11, 2 Hz, 1H),7.18 (dd, J=9, 2 Hz, 1H), 7.09 (dd, J=8, 2 Hz, 1H), 6.78 (s, 1H), 6.77(t, J=55 Hz 1H), 5.09 (br, 2H), 3.73 (s, 3H).

[2295] mS (EI): m/z 464 (M⁺)

[2296] Anal. Calcd. for C₂₀H₁₅F₃N₄O₂S₂ 0.25H₂O: C, 51.22; H, 3.33; N,11.95. Found: C, 51.14; H, 3.45; N, 11.77.

Example 196

[2297]2-Fluoro-4-[5-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[2298] 2-Bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (Step 1)

[2299] To a stirred solution of 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone(2.0 g, 12.98 mmol) in dioxane (3 ml) was added a solution of bromine(2.09 g, 13.1 mmol) in dioxane (12 ml), and the mixture was stirred for16 hours. The mixture was concentrated in vacuo to give title compound(3.02 g, 99% yield). The compound was used for next reaction withoutpurification.

[2300]¹H-NMR (DMSO-4d₆) δ: 7.85-7.75 (m, 2H), 7.14-7.08 (m, 1H), 4.85(s, 2H).

[2301] 2-Fluoro-4-(1,3-thiazol-4-yl)phenol (Step 2)

[2302] To a stirred solution of phosphorus pentasulfide (8.6 g, 19.3mmol) in dioxane (53 ml) was added formamide (5.2 g, 115.5 mmol), andthe mixture was heated at reflux temperature for 2 hours. The mixturewas cooled down to room temperature, and the solution was decanted awayfrom solids. To a stirred solution of2-bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (3.02 g, 12.98 mmol) indioxane (50 ml) was added the thioformamide solution, and the mixturewas heated at reflux temperature for 6 hours. The mixture was cooleddown to room temperature, and made basic by addition of 0.5M NaOHaqueous solution. The whole was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate-hexane (1:3) to give title compound (2.11 g, 83% yield).

[2303]¹H-NMR (CDCl₃) δ: 8.87 (d, J=2 Hz, 1H), 7.67 (d, J=12 Hz. 1H),7.57 (d, J=8 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.07-7.01 (m, 1H), 6.18 (s,1H).

[2304] 2-Fluoro-4-(13-thiazol-4-yl)phenyl trifluoromethanesulfonate(Step 3)

[2305] To a stirred solution of 2-fluoro-4-(1,3-thiazol-4-yl)phenol(2.11 g, 10.81 mmol), triethylamine (1.31 g, 12.97 mmol) in CH₂Cl₂ (65ml) was added trifluoromethanesulfonic anhydride (3.35 g, 11.89 mmol) at0° C., and the mixture was stirred for 1 hour. The mixture was dilutedwith water, and the whole was extracted with CH₂Cl₂. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:4) to give title compound (3.47 g, 98% yield).

[2306]¹H-NMR (CDCl₃) δ: 8.89 (d, J=2 Hz, 1H), 7.87 (dd, J=11, 2 Hz, 1H);7.76 (ddd, J=9, 2, 1 Hz, 1H), 7.62 (d, J=2 Hz, 1H), 7.43-7.37 (m, 1H).

[2307] 1-[2-Fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 4)

[2308] To a stirred solution of 2-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate (3.47 g, 10.6 mmol) in DMF (11.7 ml) was addedtriethylamine (1.29 g, 12.72 mmol), butyl vinyl ether (5.31 g, 53 mmol),1,3-bis(diphenylphosphino)propane (240 mg, 0.583 mmol), palladiumacetate (120 mg, 0.53 mmol) successively, and the mixture was heated at80° c. for 5 hours. The mixture was cooled down to room temperature. 2NHCl aqueous solution (30 ml) was added, and the mixture was stirred for1 hour. The mixture was made neutral by addition of NaHCO₃, andextracted with ethyl acetate. The organic layer was washed with water,brine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate-hexane (1:4)to give title compound (2.03 g, 87% yield).

[2309]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H). 7.98-7.92 (m, 1H),7.78-7.76 (m, 1H), 7.73 (d, J=1 Hz, 1H), 7.71 (d, J=2 Hz, 1H), 2.67 (d,J=5 Hz, 3H).

[2310]4,4,4-Trifluoro-1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 5)

[2311] To a stirred solution of1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (2.03 g, 9.18 mmol)in t-butylmethylether (60 ml) was added ethyl trifluoroacetate (1.56 g,11.01 mmol), sodium methoxide (28 wt. % solution in methanol; 2.49 ml,11.01 mmol) at 0° c., and the mixture was stirred for 3 hours. Themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, and concentrated in vacuo to give titlecompound (2.92 g, 99% yield). The compound was used for next reactionwithout purification.

[2312]¹H-NMR (DMSO-d₆) δ: 9.23-9.21 (m, 1H), 8.44-8.27 (m, 1H),7.96-7.81 (m, 3H), 6.23-6.17 (m, 1H).

[2313]2-Fluoro-4-[5-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 6)

[2314] To a stirred solution of4,4,4-trifluoro-1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(349 mg, 1.1 mmol) in ethanol (13.8 ml) was added2-fluoro-4-hydradinobenzenesulfonamide hydrochloride (292 mg, 1.21mmol), and the mixture was heated at reflux temperature for 16 hours.The mixture was cooled down to room temperature, and concentrated invacuo. The residue was dissolved in ethyl acetate, washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography eluting with ethyl acetate/hexane (1/3-1/2). Theresulting solid was recrystallized with diisopropyl ether-hexane to givetitle compound (326 mg, 61% yield).

[2315]¹H-NMR (DMSO-d₆) δ: 9.13 (d, J=2 Hz, 1H), 8.30 (d, J=2 Hz, 1H),7.88-7.71 (m, 5H), 7.52-7.45 (m, 2H), 7.27-7.25 (m, 2H).

[2316] mS (EI): m/z 486 (M⁺)

Example 197

[2317]2-Fluoro-4-[5-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[2318] 2-Bromo-1-(3-chloro-4-hydroxyphenyl)-1-ethanone (Step 1)

[2319] The title compound was prepared according to the procedure ofExample 196 (step 1) using 1-(3-chloro-4-hydroxyphenyl)-1-ethanoneinstead of 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone.

[2320]¹H-NMR (DMSO-d₆) δ: 7.99-7.67 (m, 2H), 7.00-6.94 (m, 1H), 4.71 (s,2H).

[2321] 2-Chloro-4-(1,3-thiazol-4′-yl)phenol (Step 2)

[2322] The title compound was prepared according to the procedure ofExample 196 (step 2) using2-bromo-1-(3-chloro-4-hydroxyphenyl)-1-ethanone instead of2-bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone.

[2323]¹H-NMR (CDCl₃) δ: 8.86 (d, J=2 Hz, 1H), 7.93 (d, J=2 Hz, 1H), 7.70(dd, J=8, 2 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.22(s, 1H).

[2324] 2-Chloro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate(Step 3)

[2325] The title compound was prepared according to the procedure ofExample 196 (step 3) using 2-chloro-4-(1,3-thiazol-4-yl)phenol insteadof 2-fluoro-4-(1,3-thiazol-4-yl)phenol.

[2326]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.13 (d, J=2 Hz, 1H), 7.89(dd, J=9, 2 Hz, 1H), 7.62 (d, J=2 Hz, 1H), 7.42 (d, J=9 Hz, 1H).

[2327] 1-[2-Chloro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 4)

[2328] The title compound was prepared according to the procedure ofExample 196 (step 4) using 2-chloro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate instead of 2-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate.

[2329]¹H-NMR (CDCl₃) δ: 8.90 (d, J=2 Hz, 1H), 8.03 (d, J=2 Hz, 1H), 7.86(dd, J=8, 2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 2.69(s, 3H).

[2330]4,4,4-Trifluoro-1-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 5)

[2331] The title compound was prepared according to the procedure ofExample 196 (step 5) using1-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone instead of1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone.

[2332]¹H-NMR (CDCl₃) δ: 8.92 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=9 Hz,1H), 7.79 (d, J=8 Hz, 1H), 7.72 (s, 1H), 6.67 (s, 1H).

[2333]2-Fluoro-4-[5-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 6)

[2334] The title compound was prepared according to the procedure ofExample 196 (step 6) using4,4,4-trifluoro-1-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedioneinstead of4,4,4-trifluoro-1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione.

[2335]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H), 7.93(dd, J=8, 2 Hz, 1H), 7.84-7.78 (m, 1H), 7.70 (d, J=2 Hz, 1H), 7.41 (d,J=8 Hz, 1H), 7.36 (dd, J=11, 2 Hz, 1H), 7.13 (d, J=9 Hz, 1H), 6.84 (s,1H), 5.12 (s, 2H).

[2336] mS (EI): m/z 502 (M⁺)

Example 198

[2337]2-Fluoro-4-[5-[3-ethyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

[2338] 4-Bromo-2-ethylphenol (Step 1)

[2339] To a stirred solution of 2-ethylphenol (8.97 g, 73.4 mmol) inacetic acid (100 ml) was added hydrobromic acid (48 wt. % solution inwater; 50 ml, 442 mmol), DMSO (50 ml, 705 mmol) dropwise, and themixture was stirred for 1 hour. The mixture was diluted with water, andthe whole was extracted with diethylether. The organic layer was washedwith saturated NaHCO₃ aqueous solution, brine, dried over MgSO₄, andconcentrated in vacuo to give title compound (15.2 g, 99% yield). Thecompound was used for next reaction without purification.

[2340]¹H-NMR (CDCl₃) δ: 7.24 (d, J=3 Hz, 1H), 7.16 (dd, J=9, 3 Hz, 1H),6.64, (d, J=8 Hz, 1H), 2.60 (q, J=8 Hz, 2H), 1.22 (t, J=8 Hz, 3H).

[2341] 4-Bromo-2-ethylphenyl trifluoromethanesulfonate (Step 2)

[2342] The title compound was prepared according to the procedure ofExample 196 (step 3) using 4-bromo-2-ethylphenol instead of2-fluoro-4-(1,3-thiazol-4-yl)phenol.

[2343]¹H-NMR (CDCl₃) δ: 7.48 (d, J=2 Hz, 1H), 7.39 (dd, J=9, 3 Hz, 1H),7.12 (d, J=9 Hz, 1H), 2.72 (q, J=8 Hz, 2H), 1.27 (t, J=8 Hz, 3H).

[2344] 1-(4-Bromo-2-ethylphenyl)-1-ethanone (Step 3)

[2345] The title compound was prepared according to the procedure ofExample 196 (step 4) using 4-bromo-2-ethylphenyltrifluoromethanesulfonate instead of 2-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate.

[2346]¹H-NMR (CDCl₃) δ: 7.50 (d, J=8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.39(dd, J=8, 2 Hz, 1H), 2.85 (q, J=7 Hz, 2H), 2.56 (s, 3H), 1.21 (t, J=7Hz, 3H).

[2347] 2-Bromo-1-(4-bromo-2-ethylphenyl)-1-ethanone (Step 4)

[2348] The title compound was prepared according to the procedure ofExample 196 (step 1) using 1-(4-bromo-2-ethylphenyl)-1-ethanone insteadof 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone.

[2349]¹H-NMR (CDCl₃) δ: 7.50-7.47 (m, 2H), 7.43 (dd, J=8, 2 Hz, 1H),4.36 (s, 2H), 2.83 (q, J=7 Hz, 2H), 1.23 (t, J=7 Hz, 3H).

[2350] 4-(4-Bromo-2-ethylphenyl)-1,3-thiazole (Step 5)

[2351] The title compound was prepared according to the procedure ofExample 196 (step 2) using 2-bromo-1-(4-bromo-2-ethylphenyl)-1-ethanoneinstead of 2-bromo-1-(3-fluoro-4-hydroxyphenyl)-1-ethanone.

[2352]¹H-NMR (CDCl₃) δ: 8.88 (d, J=2 Hz, 1H), 7.47-7.36 (m, 3H), 7.31(d, J=2 Hz, 1H), 2.76 (q, J=8 Hz, 2H), 1.15 (t, J=7 Hz, 3H).

[2353] 1-[3-Ethyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 6)

[2354] To a stirred solution of 4-(4-bromo-2-ethylphenyl)-1,3-thiazole(2.35 g, 8.76 mmol) in dioxane (45 ml) was addedtributyl(1-ethoxyvinyl)tin (3.48 g, 9.64 mmol),tetrakis(triphenylphosphine)palladium (1010 mg, 0.876 mmol), lithiumchloride (928 mg, 21.9 mmol), and the mixture was heated at refluxtemperature for 16 hours. The reaction mixture was cooled down to roomtemperature, and diluted with ethyl acetate. The whole was washed withsaturated potassium fluoride aqueous solution, and the precipitate wasremoved by filteration through celite. The resulting solution wasextracted with ethyl acetate. The organic layer was concentrated invacuo. To the residue was added THF (15 ml), 2N HCl aqueous solution (15ml), and the mixture was heated at reflux temperature for 8 hours. Thereaction mixture was cooled down to room temperature, made neutral byaddition of NaHCO₃, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:5) to give title compound (1.51 g, 74% yield).

[2355]¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.93 (d, J=2 Hz, 1H), 7.83(dd, J=8, 2 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.40 (d, J=2 Hz, 1H), 2.87(q, J=8 Hz, 2H), 2.64 (s, 3H), 1.91 (t, J=8 Hz, 3H).

[2356]1-[3-Ethyl-4-(1,3-thiazol-4-yl)phenyl]-4,4,4-trifluoro-1,3-butanedione(Step 7)

[2357] The title compound was prepared according to the procedure ofExample 196 (step 5) using1-[3-ethyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone instead of1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone.

[2358]¹H-NMR (CDCl₃) δ: 9.05 (d, J=2 Hz, 1H), 7.92 (d, J=2 Hz, 1H), 7.83(dd, J=8, 2 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 6.61(s, 1H), 2.86 (q, J=7 Hz, 2H), 1.20 (t, J=8 Hz, 3H).

[2359]2-Fluoro-4-[5-[3-ethyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide(Step 8)

[2360] The title compound was prepared according to the procedure ofExample 196 (step 6) using1-[3-ethyl-4-(1,3-thiazol-4-yl)phenyl]-4,4,4-trifluoro-1,3-butanedioneinstead of4,4,4-trifluoro-]-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione.

[2361]¹H-NMR (CDCl₃) δ: 8.89 (d, J=2 Hz, 1H), 7.85-7.79 (m, 1H), 7.50(d, J=8 Hz, 1H), 7.38 (d, J=2 Hz, 1H), 7.35 (dd, J=11, 2 Hz, 1H), 7.23(d, J=2 Hz, 1H), 7.17 (dd, J=9, 2 Hz, 1H), 7.09 (d, J=8, 2 Hz, 1H), 6.82(s, 1H), 5.71 (d, J=5 Hz, 2H), 2.76 (q, J=7 Hz, 2H), 1.06 (t, J=8 Hz,3H).

[2362] mS (EI): m/z 496 (M⁺)

[2363] The chemical structures of the compounds prepared in the Examples1 to 198 are summarized in the following tables. TABLE (I)

Ex.# A R¹ R² R³ R⁴ R⁵ R⁶ R⁷ 1 pyrazole 2-thienyl methyl 3-CF₃ H — H H 2pyrazole 3-thienyl methyl 3-CF₃ H — H H 3 pyrazole 2-furyl methyl 3-CF₃H — H H 4 pyrazole 4-benzo[b]- methyl 3-CF₃ H — H H furan-2-yl 5pyrazole 3-thienyl amino 3-CF₃ H — H H 6 pyrazole 3-thienyl amino4-cyano H — H H 7 pyrazole 4-pyridyl amino 3-CF₃ H — H H 8 pyrazole3-pyridyl amino 3-CF₃ H — H H 9 pyrazole 5-methyl-2-thienyl amino 3-CF₃H — H H 10 pyrazole 3-furyl amino 3-CF₃ H — H H 11 pyrazole5-pyrimidinyl amino 3-CF₃ H — H H 12 pyrazole 2-pyrrolyl amino 3-CF₃ H —H H 13 pyrazole 2-benzothienyl amino 3-CF₃ H — H H 14 pyrazole 5-acetyl-amino 3-CF₃ H — H H thiohene-2-yl 15 pyrazole 3-pyrrolyl amino 3-CF₃ H —H H 16 pyrazole 3-methyl- amino 3-CF₃ H — H H 2-thienyl 17 pyrazole3-thienyl amino 3-CO₂CH₃ H — H H 18 pyrazole 5-thienyl amino 3-CH₂CN H —H H 19 pyrazole 3-thienyl amino 3-CH₂OH H — H H 20 pyrazole 3-furylmethyl 3-CF₃ H — H H 21 pyrazole 2-thiazolyl amino 3-CF₃ H — H H 22pyrazole 2-thiazolyl methyl 3-CF₃ H — H H 23 pyrazole 5-thiazolyl amino3-CF₃ H — H H 24 pyrazole 5-thiazolyl methyl 3-CF₃ H — H H 25 pyrazole5-Cl-2-thienyl amino 3-CF₃ H — H H 26 pyrazole imidazolyl amino 3-CF₃ H— H H 27 pyrazole 2,5-dimethyl- amino 3-CF₃ H — H H pyrrol-1-yl 28pyrazole 2-thienyl amino 3-CF₃ H — H H 29 pyrazole 2-furyl amino 3-CF₃ H— H H 30 pyrazole 2-furyl amino 3-CF₃ H — H 3-methyl 31 pyrazole 2-furylmethyl 3-CF₃ H — H 3-methyl 32 2-furanone 3-thienyl methyl H H — H H 332-furanone 2-thienyl methyl H H — H H 34 2-furanone 3-furyl methyl H H —H H 35 pyrrole 2-furyl methyl 2-methyl H H 3-F H 36 pyrrole 3-furylmethyl 2-methyl H H 3-F H 37 pyrrole 3-furyl methyl 2-methyl 3-methyl HH H 38 pyrrole 3-furyl methyl 2-methyl H H H H 39 pyrrole 3-furyl methyl2-methyl H H H 3-methyl 40 pyrrole 2-furyl methyl 2-methyl H H H3-methyl 41 pyrrole 3-furyl methyl 2-methyl H H H 3-Cl 42 pyrrole2-furyl methyl 2-methyl H H H 3-Cl 43 pyrrole phenyl methyl 2-methyl H HH H 44 pyrrole 2-furyl methyl 2-methyl H H H H 45 pyrrole 2-thienylmethyl 2-methyl H H H H 46 pyrrole 3-thienyl methyl 2-methyl H H H H 47pyrrole 2-pyrrolyl methyl 2-methyl H H H H 48 pyrrole 1-(CH₃)₃C—OC(O)-methyl 2-methyl H H H H 2-pyrrolyl 49 pyrrole 2-thiazolyl methyl2-methyl H H H H 50 oxazole 2-thienyl methyl 2-methyl — — H H 51 oxazole2-furyl methyl 2-methyl — — H H 52 imidazole 2-thienyl methyl 4-CF₃ H —H H 53 imidazole 2-furyl methyl 4-CF₃ H — H H 54 pyrrole 2-furyl amino4-methyl H H H H 55 pyrrole 3-furyl methyl 4-methyl H H H H 56 pyrrole3-furyl methyl 4-methyl H H H H 57 pyrrole phenyl methyl 4-methyl H H HH 58 pyrrole 2-furyl methyl 4-methyl H H H H 59 pyrrole 2-furyl methyl4-methyl H H H H 60 pyrazole 2-furyl methyl 3-CF₃ H — 3-F H 61 pyrazole2-furyl CFH₂ 3-CF₃ H — H H 62 pyrazole 2-furyl methyl 4-cyano H — H H 63pyrazole 2-furyl methyl 3-CH₂OH H — H H 64 pyrazole 2-furyl methyl3-CH₂CN H — H H 65 pyrazole 2-furyl methyl 3-CO₂C₂H₅ H — H H 66 pyrazole1-imidazolyl methyl 3-CF₃ H — H H 67 pyrazole 2-furyl methyl 3-COOH H —H H 68 thiophene 2-furyl methyl H H — H H 69 thiophene 3-furyl methyl HH — H H 70 pyrazole 2-furyl amino 3-CF₃ H — H 3-Cl 71 pyrazole 2-furylmethyl 3-CF₃ H — H 3-Cl 72 pyrazole 2-furyl amino 3-CF₃ H — H 3-methoxy73 pyrazole 2-furyl amino 3-CF₃ H — H 3-F 74 pyrazole 2-furyl methyl3-CF₃ H — H 3-F 75 pyrazole 5-oxazolyl amino 3-CF₃ H — H H 76 pyrazole5-oxazolyl methyl 3-CF₃ H — H H 77 pyrazole 2-furyl amino 3-CF₃ H — H2-methyl 78 pyrazole 2-furyl methyl 3-CF₃ H — H 2-methyl 79 pyrazole2-furyl amino 3-CF₃ H — H 2-F 80 pyrazole 2-furyl methyl 3-CF₃ H — H 2-F81 pyrazole 2-furyl methyl 3-CF₃ H — H 3-methoxy 82 pyrazole 4-thiazolylmethyl 3-CF₃ H — H H 83 pyrazole 2-furyl methyl 3-CF₃ H — 3-F 3-methyl84 pyrazole 5-oxazolyl methyl 3-CF₃ H — 3-F H 85 pyrazole 3-furyl methyl3-CF₃ H — 3-F H 86 pyrazole 2-thienyl methyl 3-CF₃ H — 3-F H 87 pyrazole3-thienyl methyl 3-CF₃ H — 3-F H 88 pyrazole 2-thiazolyl amino 3-CO₂CH₃H — H H 89 pyrazole 2-thiazolyl amino 4-cyano H — H H 90 pyrazole2-thiazolyl amino 3-CF₃ 4-Cl — H H 91 pyrazole 2-furyl methyl 3-CF₃ H —3-F 2-F 92 pyrazole 2-furyl methyl 3-CF₃ H — 3-F 2-CH₃ 93 pyrazole2-furyl methyl 3-CF₃ H — 3-F 3-Cl 94 pyrazole 1,3-oxazol-4-yl methyl3-CF₃ H — 3-F H 95 pyrazole 1,3-oxazol-4-yl methyl 3-CF₃ H — H H 96pyrazole 1,3-oxazol-2-yl methyl 3-CF₃ H — 3-F H 97 pyrazole1,3-oxazol-2-yl methyl 3-CF₃ H — H H 98 pyrazole 1,3-oxazol-2-yl amino3-CF₃ H — H H 99 pyrazole 1,3-thiazol-4-yl methyl 3-CF₃ H — 3-F H 100pyrazole 1,3-thiazol-4-yl amino 3-CF₃ H — H H 101 pyrazole1,3-thiazol-4-yl amino 3-CF₃ H — 3-CH₃ H 102 pyrazole 2-methyl- methyl3-CF₃ H — 3-F H 1,3-thiazol-4-yl 103 pyrazole 1,3-thiazol-4-yl amino3-CF₃ H — 3-F H 104 pyrazole 5-methyl- methyl 3-CF₃ H — 3-F H1,3-thiazol-4-yl 105 pyrazole 1,3-thiazol-4-yl methyl 3-CF₃ H — 3-F 3-F106 pyrazole 1,3-thiazol-4-yl methyl 3-CF₃ H — 3-F 3-CH₃ 107 pyrazole1,3-thiazol-4-yl methyl 3-CF₃ H — 3-F 3-CH₃O 108 pyrazole1,3-oxazol-4-yl methyl 3-CF₃ H — 3-F 3-CH₃O 109 pyrazole1,3-thiazol-4-yl methyl 3-CF₃ H — 3-F 3-Cl 110 pyrazole 1,3-oxazol-4-ylmethyl 3-CF₃ H — 3-F 3-CH₃ 111 pyrazole 1,3-oxazol-4-yl methyl 3-CF₃ H —H 3-CH₃O 112 pyrazole 1,3-oxazol-4-yl methyl 3-CF₃ H — H 3-CH₃ 113pyrazole 1,3-thiazol-4-yl amino 3-CF₃ H — 3-F 3-CH₃ 114 pyrazole1,3-thiazol-4-yl amino 3-CF₃ H — 3-F 3-F 115 pyrazole 1,3-thiazol-4-ylmethyl 3-CF₃ H — 3-HOCH₂ H 116 pyrazole 1,3-oxazol-4-yl amino 3-CF₃ H —H 3-CH₃ 117 pyrazole 1,3-oxazol-4-yl amino 3-CF₃ H — H 3-CH₃O 118pyrazole 1,3-oxazol-4-yl amino 3-CF₃ H — H H 119 pyrazole1,3-thiazol-4-yl methyl 3-CF₃ H — H 3-Cl 120 pyrazole 1,3-thiazol-4-ylmethyl 3-CF₃ H — H 3-CH₃O 121 pyrazole 1,3-oxazol-4-yl amino 3-CF₃ H —3-F H 122 pyrazole 1,3-thiazol-4-yl amino 3-CF₃ H — 3-F 3-Cl 123pyrazole 1,3-oxazol-4-yl amino 3-CF₃ H — 3-F 3-CH₃ 124 pyrazole1,3-thiazol-4-yl methyl 3-CF₃ H — H 3-F 125 pyrazole 1,3-thiazol-4-ylmethyl 3-CF₃ H — H 3-CH₃ 126 pyrazole 2-furyl methyl 3-C₂H₅OC(O)— H —3-F H 127 pyrazole 2-furyl methyl 3-COOH H — 3-ethoxy H 128 pyrazole2-furyl methyl 3-COOH H — 3-F H 129 pyrazole 2-furyl methyl 3-HOCH₂— H —3-F H 130 pyrazole 2-furyl methyl 3-morpholino- H — 3-F H carbonyl 131pyrazole 2-furyl methyl 3-CH₃NHC(O)— H — 3-F H 132 pyrazole 2-furylmethyl 3-NH₂C(O)— H — 3-F H 133 pyrazole 2-furyl methyl 3-(CH₃)₂NC(O)— H— 3-F H 134 pyrazole 2-furyl methyl 3-CH₃ONHC(O)— H — 3-F H 135 pyrazole2-furyl methyl 3-CF₃ H — 3-CF₃ H 136 pyrazole 2-furyl methyl 3-CF₃ H —3-CH₃O H 137 pyrazole 2-furyl amino 3-CF₃ H — 3-F H 138 pyrazole 2-furylamino 3-CF₃ H — 3-F 3-Cl 139 pyrazole 2-furyl amino 3-CF₃ H — 3-F 3-CH₃140 pyrazole 2-furyl amino 3-CF₃ H — 2-Cl H 141 pyrazole 2-furyl amino3-CF₃ H — 2-F H 142 pyrazole 2-furyl methyl 3-CF₃ H — 2-CH₃ H 143pyrazole 2-furyl amino 3-CF₃ H — 3-CH₃ H 144 pyrazole 2-furyl amino3-CF₃ H — 3-Cl H 145 pyrazole 2-furyl amino 3-CF₃ H — 2-CH₃ H 146pyrazole 2-furyl methyl 3-CF₃ H — 3-CH₃O H 147 pyrazole 2-furyl methyl3-CF₃ H — 2-CF₃ H 148 pyrazole 2-furyl amino 3-CF₃ H — 3-CH₃O H 149pyrazole 1,3-thiazol-4-yl amino 3-CF₃ H — 3-Cl 3-CH₃ 150 pyrazole1,3-thiazol-4-yl amino 3-CF₃ H — 2-F 3-CH₃ 151 pyrrole 1,3-thiazol-4-ylmethyl 5-CH₃ H H 3-F H 152 pyrrole 1,3-thiazol-4-yl methyl 5-CH₃ H H 3-F3-CH₃ 153 pyrazole 1,3-thiazol-4-yl methyl 2-CF₃ H — 3-F H 154 pyrazole1,3-thiazol-4-yl amino 3-CF₃ H — 3-F H 155 pyrazole 2-furyl methyl 3-CF₃H — 3-Cl H 156 pyrazole 2-furyl methyl 3-CF₃ H — 3-HOCH₂ H 157 pyrazole2-furyl methyl 3-CF₃ H — 3-CH₃ H 158 pyrazole 1,3-thiazol-4-yl methyl3-CF₃ H — 3-Cl H 159 pyrazole 2-furyl methyl 3-CF₃ H — 3-CH₃OCH₂ H 160pyrazole 2-furyl methyl 3-CF₃ H — 3-CH₃NH— H CH₂— 161 pyrazole 2-furylmethyl 3-CF₃ H — 3-NH₂CH₂ 162 pyrazole 2-furyl methyl H H — 3-F H 163pyrazole 2-furyl methyl 4-cyano H — 3-F H 164 pyrazole 1,3-thiazol-4-ylmethyl 4-CH₃C(O)NH H — 3-F H 165 2-furanone 1,3-thiazol-4-yl methyl H H— 3-F H 166 2-furanone 1,3-thiazol-4-yl methyl 5-CH₃ 5-CH₃ — H H 1672-furanone 1,3-thiazol-4-yl amino H H — 3-F H 168 isoxazole1,3-thiazol-4-yl methyl 5-CH₃ — — 3-F H 169 1,3-oxazole 1,3-thiazol-4-ylmethyl 2-CH₃ — — 3-F H 170 isoxazole 1,3-thiazol-4-yl methyl 5-CH₃ — —3-F 3-CH₃ 171 isoxazole 1,3-thiazol-4-yl amino 5-CH₃ — — H H 172isoxazole 1,3-thiazol-4-yl amino 5-CH₃ — — 2-F H 173 1,3-oxazole1,3-thiazol-4-yl methyl 5-CH₃ — — 3-F 3-CH₃ 174 pyrazole1,3-thiazol-4-yl amino 3-CF₃ H — 3-OH 3-F 175 pyrazole 1,3-thiazol-4-ylamino 3-CF₃ H — 3-CH₃O 3-F 176 pyrazole 1,3-thiazol-4-yl amino 3-CF₃4-Cl — 3-CF₃ 3-F 177 pyrazole 1,3-thiazol-4-yl methyl 3-CF₃ H — 3-C₂H₅3-F 178 pyrazole 1,3-thiazol-4-yl methyl 3-CF₃ H — 3-F 3-CH₃ 179pyrazole imidazolyl amino 4-CH₃ H — 3-F H 180 pyrazole 1,3-thiazol-4-ylmethyl 3-CF₃ H — 3-Cl, 5-CH₃ 3-F 181 pyrazole 1,3-thiazol-4-yl methyl3-CF₃ 4-Cl — 3-CH₃ 3-F 182 2-furanone 1,3-thiazol-4-yl methyl H H — H H183 2-furanone 1,3-thiazol-4-yl amino H H — H H 184 2-furanone1,3-thiazol-4-yl methyl 5-CH₃ 5-CH₃ — 3-CH₃ H 185 1,3-thiazole1,3-thiazol-4-yl methyl 2-CH₃ — — H H 186 pyrazole 1,3-thiazol-4-ylmethyl 3-CF₃ H H 2-CH₃ H 187 pyrazole 1,3-thiazol-4-yl methyl 3-CF₃ H H3-F 2-CH₃ 188 isoxazole 1,3-thiazol-4-yl amino 5-CH₃ — — 3-F 3-CH₃ 189isoxazole 1,3-thiazol-4-yl methyl 5-CH₃ — — H H 190 isoxazole1,3-thiazol-4-yl amino 5-CH₃ — — H H 191 isoxazole 1,3-thiazol-4-ylmethyl 3-CH₃ — — H H 192 1,3-oxazole 1,3-thiazol-4-yl amino 2-CH₃ — —3-F H 193 isoxazole 1,3-thiazol-4-yl amino 2-CH₃ — — 3-F H 194 pyrazole1,3-thiazol-4-yl methyl 3-CHF₂ — — 3-F 3-CH₃ 195 pyrazole1,3-thiazoly-4-yl amino 3-CF₂H H — 3-F 3-CH₃ 196 pyrazole1,3-thiazoly-4-yl amino 3-CF₃ H — 3-F 2-F 197 pyrazole 1,3-thiazoly-4-ylamino 3-CF₃ H — 3-F 2-Cl 198 pyrazole 1,3-thiazoly-4-yl amino 3-CF₃ H —3-F 3-C₂H₅

1. A compound of the formula:

or its pharmaceutically acceptable salt thereof, wherein A is partiallyunsaturated or unsaturated five membered heterocyclic, or partiallyunsaturated or unsaturated five membered carbocyclic, wherein the4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (1) areattached to ring atoms of Ring A adjacent to each other; R¹ is aryl orheteroaryl, and the aryl or heteroaryl being optionally substituted byone to four substituents selected from halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkyl carbonyl, hydroxy,nitro, cyano and amino, with the proviso that when A is pyrazole, R¹ isheteroaryl; R² is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄alkylamino, C₁₋₄ dialkylamino or amino; R³, R⁴ and R⁵ are independentlyhydrogen, halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₅ alkenyl,C₂₋₅ alkynyl, C₁₋₄ alkoxy, hydroxy-CIA alkyl, C₁₋₄ alkoxy C₁₋₄ alkyl,C₁₋₄ alkanoyl, cyano, nitro, cyano C₁₋₄ alkyl, carboxy, C₁₋₄alkoxycarbonyl, aminocarbonyl, N—C₁₋₄ alkylaminocarbonyl, N,N-di-C₁₋₄alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N—C₁₋₄alkyl-N-arylamiocarbonyl, aryl, aryloxy, aryloxy-C₁₋₄ alkyl, heteroaryl,heteroaryloxy, heteroaryloxy-C₁₋₄ alkyl, morpholino-carbonyl, C₁₋₄alkoxyaminocarbonyl or C₁₋₄ alkyl-carbonylamino; or two of R³, R⁴ and R⁵are taken together with atoms to which they are attached and form a 4-7membered ring; R⁶ and R⁷ are independently hydrogen, halo, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, N,N-di N₁₋₄ alkylamino, hydroxyl-C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl, C₁₋₄ alkyl-C₁₋₄ alkoxy, C₁₋₄ alkylamino-C₁₋₄ alkyl,hydroxy, amino-C₁₋₄ alkyl and N,N-di C₁₋₄ alkylamino-C₁₋₄ alkyl; and mand n are independently 1, 2, 3 or
 4. 2. A compound according to claim1, wherein A is partially unsaturated or unsaturated five memberedheterocyclic.
 3. A compound according to claim 2, wherein A is thienyl,oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyrazolyl, oxolinyl, thiolinyl, pyrazolinyl, imidazolinyl,pyrrolinyl or furanone.
 4. A compound according to claim 3, wherein A isthienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, pyrazolyl or furanone; and R³, R⁴ and R⁵ are independentlyhydrogen, halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₅ alkenyl,C₂₋₅ alkynyl, C₁₋₄ alkoxy, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxy C₁₋₄ alkyl,C₁₋₄ alkanoyl, cyano, nitro, cyano C₁₋₄ alkyl, carboxyl, C₁₋₄alkoxycarbonyl, aminocarbonyl, N—C₁₋₄ alkylaminocarbonyl, N,N-di-C₁₋₄alkylaminocarbonyl, morpholino-carbonyl, C₁₋₄ alkoxyaminocarbonyl orC₁₋₄ alkyl-carbonylamino.
 5. A compound according to claim 4, wherein Ais thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl,isoxazolyl, pyrazolyl or furanone; R¹ is phenyl or heteroaryl selectedfrom pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl,tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazole, quinolyl,isoquinolyl, benzo[b]thienyl, benzo[b]furyl and indolyl, and the phenylor heteroaryl being optionally substituted by one to three substituentsselected from halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkyl carbonyl, C₁₋₅ alkoxycarbonyl, hydroxy, nitro, cyanoand amino; R² is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl or amino; R³,R⁴ and R⁵ are independently hydrogen, halo, C₁₋₄ alkyl, halo-substitutedC₁₋₄ alkyl, C₂₋₅ alkenyl, C₁₋₄ alkoxy, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl, C₁₋₄ alkanoyl, cyano, nitro, cyano C₁₋₄ alkyl, carboxy, C₁₋₄alkoxycarbonyl, aminocarbonyl, morpholino-carbonyl, C₁₋₄alkoxyaminocarbonyl or C₁₋₄ alkyl-carbonylamino; and R⁶ and R⁷ areindependently hydrogen, halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, hydroxyl-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, C₁₋₄ alkyl-C₁₋₄ alkoxy, C₁₋₄ alkylamino-C₁₋₄ alkyl or hydroxy;and m and n are independently 1 or
 2. 6. A compound according to claim5, wherein A is thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl,imidazolyl, isooxazolyl, pyrazolyl or furanone; R¹ is phenyl orheteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl,pyrazolyl, benzo[b]thienyl, benzo[b]furyl and indolyl, and the phenyl orheteroaryl being optionally substituted by halo, C₁₋₄ alkyl, C₁₋₄ alkylcarbonyl or C₁₋₄ alkoxy carbonyl; R² is methyl, ethyl, fluoromethyl,difluoromethyl or amino; R³, R⁴ and R⁵ are independently hydrogen, halo,C₁₋₄ alkyl, fluoro-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy-C₁₋₄alkyl, C₁₋₄ alkanoyl, cyano, nitro, cyano C₁₋₄ alkyl, carboxy, C₁₋₄alkoxycarbonyl, morpholino-carbonyl, C₁₋₄ alkoxyaminocarbonyl or C₁₋₄alkyl-carbonylamino; and R⁶ and R⁷ are independently hydrogen, halo,C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxyl-C₁₋₄alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkyl-C₁₋₄ alkoxy, C₁₋₄alkylamino-C₁₋₄ alkyl or hydroxy.
 7. A compound according to claim 6,wherein A is thienyl, oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl,isooxazolyl, pyrazolyl or furanone; R¹ is phenyl or heteroaryl selectedfrom pyridyl, pyrimidinyl, thienyl, furyl, imidazolyl, pyrrolyl,oxazolyl, thiazolyl, benzo[b]thienyl and benzo[b]furyl, and the phenylor heteroaryl being optionally substituted by one to three substituentsselected from fluoro, chloro, methyl, ethyl, propyl, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, methoxyl, acetyl,ethylcarbonyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl; R² ismethyl, fluoromethyl or amino; R³, R⁴, and R⁵ are independentlyhydrogen, fluoro, chloro, methyl, ethyl, propyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, ethoxyl, hydroxymethyl,hydroxyethyl, methylcarbonyl, cyano, nitro, cyanomethyl, cyanoethyl,carboxy, methoxylcarbonyl, ethoxycarbonyl, morpholinocarbonyl,methoxyaminocarbonyl or methylcarbonylamino; and R⁶ and R⁷ areindependently hydrogen, fluoro, chloro, methyl, ethyl, propyl,fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy,hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl,methylaminomethyl, methylaminoethyl, ethylaminomethyl, aminomethyl,aminoethyl or hydroxy.
 8. A compound according to claim 7, wherein A isoxazolyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl or furanone; R¹ isphenyl or heteroaryl selected from pyridyl, pyrimidinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl, thiazolyl, benzothienyl and benzofuryl,and the heteroaryl being optionally substituted by chloro or methyl; R²is methyl, fluoromethyl or amino; R³, R⁴ and R⁵ are independentlyhydrogen, methyl, trifluoromethyl, hydroxymethyl, cyano, cyanomethyl,carboxy, ethoxycaroblyl, morpholinocarbonyl, methoxyaminocarbonyl ormethylcarbonylamino; and R⁶ and R⁷ are independently hydrogen, fluoro,chloro, methyl, methoxy, hydroxymethyl, ethoxy, trifluoromethyl,methoxymethyl, methyaminomethyl, aminomethyl or hydroxy.
 9. A compoundaccording to claim 8, wherein A is pyrazolyl or furanone; R¹ isheteroaryl selected from thienyl, furyl, oxazolyl and thiazolyl; R² ismethyl or amino; R³, R⁴ and R⁵ are independently hydrogen, methyl ortrifluoromethyl; R⁶ and R⁷ are independently hydrogen, fluoro, chloro,methyl or methoxy; and m and n are
 1. 10. A compound according to claim1, selected from1-[4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-trifluoromethyl-1H-pyrazole;1-[4-(methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-trifluoromethyl-1H-pyrazole;1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-trifluoromethyl-1H-pyrazole;1-[4-(methylsulfonyl)phenyl]-5-[4-(benzo[b]furan-2-yl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(3-thienyl)phenyl]4-cyano-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(4-pyridyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(3-pyridyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(5-methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(5-pyrimidinyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(2-pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(2-benzothienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(5-acetylthiophene-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(3-pyrrolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(3-methyl-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;methyl1-[4-(sulfamoylphenyl]-5-[4-(3-thienyl)phenyl]-1H-pyrazole-3-carboxylate;4-[3-(cyanomethyl)-5-[4-(3-thienyl)phenyll]-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[3-(hydroxymethyl)-5-[4-(3-thienyl)phenyl]-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(2-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[4-(2-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(5-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[4-(5-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(5-chloro-2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(1H-imidazol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(2,5-dimethylpyrrol-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-phenylsulfonamide;4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methylphenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;3-[4-(3-thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone;3-4-(2-thienyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone;3-[4-(3-furyl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanone;5-[3-fluoro-4-(methylsulfonyl)phenyl]-1-[4-(2-furyl)phenyl]-2-methyl-1H-pyrrole;5-[3-fluoro-4-(methylsulfonyl)phenyl]-1-[4-(3-furyl)phenyl]-2-methyl-1H-pyrrole;2,3-dimethyl-1-[4-(3-furyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;5-[4-(methylsulfonyl)phenyl]-1-[4-(3-furyl)phenyl]-2′-methyl-1H-pyrrole;1-[4-(3-furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-[4-(2-furyl)-3-methylphenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-[3-chloro-4-(3-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-[3-chloro-4-(2-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-(4-biphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-[4-(2-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole;2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thienyl)phenyl]-1H-pyrrole;2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(3-thienyl)phenyl]-1H-pyrrole;2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-pyrrolyl)phenyl]-1H-pyrrole;2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[[4-(1-tert-butoxycarbonyl)-2-pyrrolyl]phenyl]-1H-pyrrole;2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[4-(2-thiazolyl)phenyl)-1H-pyrrole;2-methyl-5-[4-(methylsulfonyl)phenyl]-4-[4-(2-thienyl)phenyl]oxazole;4-[4-(2-furyl)phenyl]-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;1-[4-(methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;2-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;2-[4-(2-furyl)phenyl]-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole;1-[4-(3-furyl)phenyl]4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole;2-[4-(3-furyl)phenyl]4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;2-biphenyl-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-[4-(2-furyl)phenyl]4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole;2-[4-(2-furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;2-[4-(2-furyl)phenyl]-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[4-(fluoromethylsulfonyl)phenyl]]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-[5-[4-(2-furyl)phenyl]-4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole;4-[5-[4-(2-furyl)phenyl]-3-hydroxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole;3-cyanomethyl-4-[5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole;ethyl5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate;5-[4-(1-imidazolyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol;5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylicacid; 2-[4-(2-furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene;2-[4-(3-furyl)phenyl]-3-[(4-methylsulfonyl)phenyl]thiophene;4-[5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-[5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[5-[3-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[3-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-[5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-[5-[4-(2-furyl)-2-methylphenyl]-3-(trifluoromethyl)-]H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-2-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole;4-[5-[2-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide;1-[4-(methylsulfonyl)phenyl]-5-[2-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[4-(methylsulfonyl)phenyl]-5-[4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(5-oxazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;methyl1-(4-sulfamoylphenyl)-5-[4-(2-thiazolyl)phenyl]-1H-pyrazole-3-carboxylate,4-[4-cyano-5-[4-(2-thiazolyl)phenyl]-1H-pyrazol-1-yl]-1-phenylsulfonamide;4-[4-chloro-5-[4-(2-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-1-phenylsulfonamide;5-[2-fluoro-4-(2-furyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)-2-methylphenyl]-3-trifluoromethyl-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;4-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;2-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;2-{4-[f-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;4-[5-[4-(1,3-oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;4-[5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{4-[1-[3-methyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-2-methyl-1,3-thiazole;2-fluoro-4-[5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-5-methyl-1,3-thiazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-fluorophenyl}-1,3-thiazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-thiazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-thiazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-oxazole;4-{2-chloro-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-oxazole;4-{2-methoxy-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;2-fluoro-4-[5-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{4-[”4-[3-hydroxymethyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-[3-methoxy-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{2-chloro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;4-{2-methoxy-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;2-fluoro-4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;-2-fluoro-4-[5-[3-chloro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;2-fluoro-4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{2-fluoro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;ethyl1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate;1-[3-ethoxy-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicacid;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylicacid;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-hydroxymethyl-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(4-morpholinecarbonyl)-1H-pyrazole;N-methyl-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;N,N-dimethyl-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;N-methoxy-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxamide;5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-3-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole;5-[4-(2-furyl)phenyl]-1-[3-methoxy-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole;2-fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-fluorobenzenesulfonamide;2-fluoro-4-[5-[4-(2-furyl)-3-methylphenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;3-chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;3-fluoro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;[5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-2-methylphenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methylbenzenesulfonamide;2-chloro-4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-methylbenzenesulfonamide;[5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-2-methoxy]phenyl]-3-trifluoromethyl-1H-pyrazole;[5-[4-(2-furyl)phenyl]-1-[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-methoxybenzenesulfonamide;2-chloro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;3-fluoro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-[4-(4-thiazolyl)phenyl]-1H-pyrrole;5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-1-[3-methyl-4-(4-thiazolyl)phenyl]-1H-pyrrole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[4-(4-thiazolyl)phenyl]4-trifluoromethyl-1H-imidazole;2-fluoro-4-[2-[4-(4-thiazolyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;1-[3-chloro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;5-[5-[4-(2-furyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanol;5-[4-(2-furyl)phenyl]-1-[3-methyl-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-chloro-4-(methylsulfonyl)phenyl]-5-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;5-[4-(2-furyl)phenyl]-1-[3-(methoxymethyl)-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;N-[5-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)benzyl]-N-methylaminehydrochloride;[5-[5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-(methylsulfonyl)phenyl]methanaminehydrochloride;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole;4-cyano-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole;N-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl]-1H-pyrazol-4-yl]acetamide;4-[3-fluoro-4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone;5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone;2-fluoro-4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-furanyl]benzenesulfonamide;4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]isoxazole;5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole;4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]isoxazole;4-{5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]-4-isoxazolyl}benzenesulfonamide;2-fluoro-4-{5-methyl-3-[4-(1,3-thiazol-4-yl)phenyl]4-isoxazolyl}benzenesulfonamide;5-[3-fluoro-4-(methylsulfonyl)phenyl]-2-methyl-4-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazole;2-fluoro-4-[5-[3-hydroxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;2-fluoro-4-[5-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;2-fluoro-4-[5-[4-(1,3-thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[2-ethyl-4-[1-[3-Fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl]-1,3-thiazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[3-methyl-4-(4-thiazolyl)phenyl]-4-trifluoromethyl-1H-imidazole;2-fluoro-4-[4-methyl-2-[4-(4-thiazolyl)phenyl]-1H-imidazol-1-yl]benzenesulfonamide;5-[3-chloro-5-methyl-4-(4-thiazolyl)phenyl]-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-chloro-1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[3-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;4-[4-(methylsulfonyl)phenyl]-3-[4-(1,3-thiazol-4-yl)phenyl]-2(5H)-furanone;4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-franyl]benzenesulfonamide;5,5-dimethyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone;2-methyl-4-[4-(methylsulfonyl)phenyl]-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-thiazole;1-[4-(methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[2-methyl-4-(4-thiazolyl)phenyl]-3-trifluoromethyl-1H-pyrazole;2-fluoro-4-[5-methyl-3-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]4-isoxazolyl]benzenesulfonamide;5-methyl-3-[4-(methylsulfonyl)phenyl]-4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole;4-[3-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]4-isoxazolyl]benzenesulfonamide;3-methyl-5-[4-(methylsulfonyl)phenyl]4-[4-(1,3-thiazol-4-yl)phenyl]isoxazole;2-fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide;2-fluoro-4-[2-methyl-5-[4-(1,3-thiazol-4-yl)phenyl]-1,3-oxazol-4-yl]benzenesulfonamide;3-(Difluoromethyl)-2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1H-pyrazol-1-yl]benzenesulfonamide;2-Fluoro-4-[5-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;2-Fluoro-4-[5-[2-chloro-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;and2-Fluoro-4-[5-[3-ethyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.11. A compound according to claim 10 selected from2-fluoro-4-[5-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl)}-1,3-thiazole;3-fluoro-4-[5-[3-methyl-4-(4-thiazolyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-{2-chloro-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-thiazole;2-fluoro-4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(3-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methylphenyl}-1,3-thiazole;-4-[5-[4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;4-[5-[3-methyl-4-(1,3-oxazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[4-(Methylsulfonyl)phenyl]-5-[3-fluoro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-Fluoro-4-(methylsulfonyl)phenyl]5-[4-(3-thienyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[4-(Methylsulfonyl)phenyl]-5-[4-(2-furyl)-3-methoxyphenyl]-3-(trifluoromethyl)-1H-pyrazole;1-[3-Fluoro-4-(methylsulfonyl)phenyl]-5-[3-chloro-4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;4-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;4-{4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-methoxyphenyl}-1,3-thiazole;4-{2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}-1,3-oxazole;2-fluoro-4-[5-oxo-4-[4-(1,3-thiazol-4-yl)phenyl]-2,5-dihydro-3-furanyl]benzenesulfonamide;and1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[4-(4-thiazolyl)phenyl]-4-trifluoromethyl1H-imidazole.
 12. A pharmaceutical composition useful for the treatmentof a medical condition in which prostaglandins are implicated aspathogens, which comprises a compound of the formula (I) of claim 1, anda pharmaceutically inert carrier.
 13. A method for the treatment of amedical condition in which prostaglandins are implicated as pathogens,in a mammalian subject, which comprises administering to saidpharmaceutical composition according to claim
 1. 14. A compound of theformula:

or its salt thereof, wherein R² is C, alkyl, halo-substituted C₁₋₄alkyl, C₁₋₄ alkylamino, C₁₋₄ dialkylamino or amino; R⁸ is independentlyhydrogen, halo, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₄ alkylamino, N,N-di C₁₋₄ alkylamino, C₁₋₄alkylamino-C₁₋₄ alkyl, N,N-di C₁₋₄ alkylamino-C₁₋₄ alkyl, C₁₋₄alkoxy-C₁₋₄ alkyl or hydroxy-C₁₋₄ alkyl; and m is 2, 3 or 4, with theproviso that R⁸ is not chloro nor trifluoromethyl.
 15. A compoundaccording to claim 14 selected from3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride;3-methoxy-4-(methylsulfonyl)phenylhydrazine hydrochloride;3-fluoro-4-sulfamoylphenylhydrozine hydrochloride;2-fluoro-4-sulfamoylphenylhydrazine hydrochloride;2-methyl-4-(methylsulfonyl)phenylhydrazine hydrochloride;3-methyl-4-sulfamoylphenylhydrozine hydrochloride;2-methyl-4-sulfamoylphenylhydrozine hydrochloride;2-methoxy-4-(methylsulfonyl)phenylhydrazine hydrochloride;2-methoxy-4-sulfamoylphenylhydrozine hydrochloride;3-hydroxymethyl-4-(methylsulfonyl)phenylhydrazine hydrochloride; and3-methyl-4-(methylsulfonyl)phenylhydrazine hydrochloride.